EPIGENETIC ANALYSIS OF IMMUNE ASSOCIATED SIGNALING ...

The Pennsylvania State University

The Graduate School

Department of Neural and Behavioral Sciences

EPIGENETIC ANALYSIS OF IMMUNE ASSOCIATED SIGNALING MOLECULES

DURING

MOUSE RETINA DEVELOPMENT

A Thesis in

Anatomy

by

Chen Yang

© 2013 Chen Yang

Submitted in Partial Fulfillment

of the Requirements

for the Degree of

Master of Science

May 2013

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The thesis of Chen Yang was reviewed and approved* by the following:

Samuel Shao-Min Zhang

Assistant Professor of Neural and Behavioral Sciences

Thesis Advisor

Colin J. Barnstable

Department Head of Neural and Behavioral Sciences

Professor of Neural and Behavioral Sciences

Patricia J. McLaughlin

Professor of Neural and Behavioral Sciences

Director of Graduate Program in Anatomy

*Signatures are on file in the Graduate School.

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ABSTRACT

The retina is an immune-privileged organ. Many autoimmune diseases, such as AMD,

glaucoma, and diabetic retinopathy, are caused by excessive inflammatory responses targeting

self-tissue. The physiological functions of extracellular and intracellular signaling molecules of

immune responses have been well characterized. The epigenetic aspects of these molecules in

the retina, however, have not been well elucidated. In this study, we examined the expression of

selected immune-related genes, and their transcriptional accessibility via epigenetic mapping,

cluster analysis, and RT-PCR. Among these genes, interleukin receptor related genes and

intracellular signaling molecules exhibit higher transcriptional accessibility. Epigenetic mapping

of the toll-like receptor (TLR) family revealed that 3 out of 13 TLRs exhibit H3K4me2

accumulation during retina development, suggesting that TLR2, TLR3, and TLR9 are the only

TLR members expressed in the retina. Most of the NF-κB signaling molecules exhibited

transcriptional accessibility, implying their essential roles in inflammatory regulation during retina

maturation. We have also identified two isoforms each of two NF-κB negative feedback regulator

genes, Tnfaip3/A20 and Pcbp2, as well as another NF-κB negative feedback regulator gene,

Trafd1, that are differentially expressed in mouse retina and spleen in response to LPS treatment.

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TABLE OF CONTENTS

Page Number

LIST OF FIGURES viii

LIST OF TABLES ix

LIST OF ABBREVIATIONS x

ACKNOWLEDGEMENTS xvi

CHAPTER 1. INTRODUCTION

1.1 Developing retina is a great model to study central nerve system 2

1.1.1 Gross Structures of retina 2

1.1.2 Histological structures of retina 2

1.1.3 Development of retina 5

1.2 Inflammation/immune response signaling is associated with retinal

pathogenesis 6

1.2.1 Diabetic retinopathy 6

1.2.2 Age-related macular degeneration (AMD) 7

1.2.3 Glaucoma 9

1.3 STAT3 is an important molecule for retinal development and retinal

stress responses 10

1.3.1 STAT expression in retina 10

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1.3.2 STAT3 is a signaling mediator for photoreceptor development 12

1.3.3 Cross-talk of PKC and STAT3 signaling in retina differentiation 13

1.3.4 STAT3 mediates stress responses in retina 14

1.4 NF-κB, the master control for inflammatory and immune responses 16

1.4.1 Basics of NF-κB 16

1.4.2 NF-κB mediated signaling 16

1.4.3 Regulation of NF-κB signaling 18

1.5 Negative feedback for NF-κB signaling 20

1.5.1 Tnfaip3/A20 is a specific ubiquitinases for NF-κB signaling 20

1.5.2 Tnfaip3/A20 is a universal inhibitor for NF-κB signaling by

varies of activators 21

1.5.3 Loss of NF-κB negative feedback and human diseases 22

1.6 Summary 24

CHAPTER 2. OBJECTIVES

2.1 Overall hypothesis 27

2.2 Specific Aim 1: Epigenetic analysis on extracellular signaling of

inflammatory/immune response genes during retina development 27

2.3 Specific Aim 2: Epigenetic analysis on intracellular signaling of

inflammatory/immune response genes during retina development 28

2.4 Specific Aim 3: Examination of NF-κB negative feedback signaling in

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retina 28

CHAPTER 3. METHODS AND MATERIALS

3.1 Animals 30

3.2 Tissue collection 30

3.2.1 Retina evisceration 30

3.2.2 Spleen isolation 30

3.3 Drug treatment 31

3.4 Retina explants culture 31

3.5 RNA extraction and purification 31

3.6 Spectrophotometry 32

3.7 RNA reverse transcription 32

3.8 Primer design and synthesis 33

3.9 Genomic-PCR / RT-PCR 34

3.10 ChIP-Seq database and data collection 35

3.11 Cluster analysis 35

3.12 Image J and densitometry analysis 36

3.13 Statistical analysis 36

CHAPTER 4. RESULTS

4.1 Epigenetic analysis on extracellular signaling of inflammatory/immune

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response genes during retina development 38

4.1.1 Introduction 38

4.1.2 Collection of genes 38

4.1.3 Epigenetic analysis 38

4.1.3.1 Cluster analysis of interleukin ligands and their receptors 38

4.1.3.2 Cluster analysis of complements 42

4.1.3.3 Epigenetic mapping of complements 44

4.1.3.4 Epigenetic mapping of Toll-like receptors 45

4.2 Epigenetic analysis on intracellular signaling of inflammatory/immune

response genes during retina development 46



4.2.3 Epigenetic analysis 47

4.2.3.1 Cluster analysis of PI3K signaling 47

4.2.3.2 Cluster analysis of STAT signaling 48

4.2.3.3 Cluster analysis of NF-κB signaling 50

4.3 Examination of NF-κB negative feedback signaling in retina 51



4.3.3 Epigenetic mapping of NF-κB negative feedback genes 51

4.3.3.1 Epigenetic mapping of NF-κB signaling genes 52

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4.3.3.2 Epigenetic mapping of NF-κB negative feedback genes 55

4.3.4 Gene expression of NF-κB negative feedback genes in retina 56

4.3.4.1 Tnfaip3/A20 expression during retina development 56

4.3.4.2 Tissue specific Tnfaip3/A20 responses to LPS 57

4.3.4.3 Differential response of other NF-κB negative feedback genes 61

CHAPTER 5. DISCUSSION AND CONCLUSION

5.1 Interleukin receptors compared to interleukin themselves have more

transcriptional accessibilities in retina 66

5.2 A number of complements are transcriptionally accessible at the

alternative transcription start site in the retina 68

5.3 The toll-like receptor family has limited transcriptional accessibilities in

the retina 69

5.4 Most of genes in NF-κB signaling pathway are transcriptionally

accessible in the retina 71

5.5 Constitutive expression of the genes related to NF-κB negative

feedback in mature retina 73

5.6 Conclusion 74

REFERENCES 75

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LIST OF FIGURES

Figure 1 PCR Scheme 34

Figure 2 Cluster analysis and Tree-view for interleukins and interleukin receptors 39

Figure 3 Bar chart for interleukin and interleukin receptor comparison 40

Figure 4 Cluster analysis and Tree-view for complements 41

Figure 5 Epigenetic mapping of complements 42

Figure 6 Epigenetic mapping of Toll-like receptors 43

Figure 7 Cluster analysis and Tree-view of PI3K-AKT signaling molecules 46

Figure 8 Cluster analysis and Tree-view of JAK-STAT signaling molecules 47

Figure 9 Cluster analysis and Tree-view of NF-κB signaling molecules 50

Figure 10 Epigenetic mapping of NF-κB signaling genes part 1 52

Figure 11 Epigenetic mapping of NF-κB signaling genes part 2 53

Figure 12 Epigenetic mapping of NF-κB negative feedback genes 54

Figure 13 Tnfaip3/A20 expression during developmental stages 55

Figure 14 Tnfaip3/A20 primer design 56

Figure 15 Tnfaip3/A20 PCR results with/without LPS treatment 57

Figure 16 Statistical analysis for Tnfaip3 expression in the retina and spleen 58

Figure 17 Pcbp2 and Trafd1 PCR results with/ without LPS treatment 59

Figure 18 Statistical analyses for Pcbp2 and Trafd1 expression in the retina

and spleen 61

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LIST OF TABLES

Table 1 Primer information 34

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LIST OF ABBREVIATIONS

A20 another name for tnfaip3

AMD age-related macular degeneration

ATP adenosine triphosphate

ATSS alternative transcription start site

AXK axokine

BCR B cell receptor

β beta

bFGF basic fibroblast growth factor

bZIP basic Leucine Zipper Domain

°C degrees Centigrade

CFH complement factor H

CNV choroidal neovascularisation

CRP C-reactive protein

CD cluster of differentiation

CD Crohn’s disease

cIAP cellular inhibitor of apoptosis

CNTF ciliary neurotrophic factor

CO2 carbon dioxide

Cre cyclization recombination

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Crx cone-rod homeobox protein

CYLD cylindromatosi

d day

DC dendritic cell

diH2O dionized water

DNA deoxyribonucleic acid

DUB deubiquitylating enzyme

et al and others

E/ED embryonic day

EGF epidermal growth factor

EGFRs epidermal growth factor receptors

ELM external limiting membrane

ERK extracellular signal-regulated kinase

FCS fetal calf serum

flox flanked by loxP

g gram

GCL ganglion cell layer

GCAP guanylatecyclase-activating protein

GFAP glial fibrillary acidic protein

gp130 glycoprotein 130

h hour

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IACUC Institutional Animal Care and Use Committee

IBD inflammatory bowel disease

IFN interferon

IGF insulin-like growth factor

IKK IκB kinase

IκB inhibitor of kappa B

ILM inner limiting membrane

IL interleukin

INL inner nuclear layer

IOP intraocular pressure

IPL inner plexiform layer

IRBP Interphotoreceptor retinoid-binding protein

JAK janus kinases

κ kappa

LIF leukemia inhibitory factor

LPS lipopolysaccharide

LUBAC E3 ligase linear ubiquitin chain assembly complex

Lys lysine

MCP monocyte chemotactic protein

MDP muramyl dipeptide

min(s) minute(s)

xiv

ml milliliter

M molar

MALT mucosa-associated tissue

MAPK mitogen-activated protein kinases

NEMO NF-kappa-B essential modulator

NFL nerve fiber layer

NPG normal pressure glaucoma

OPL outer plexiform layer

OSM oncostatin M

Otx2 orthodenticlehomeobox 2

RGCs retinal ganglion cells

RIP receptor-interacting protein

RPE retinal pigment epithelium

μ mu

MEF mouse embryonic fibroblast

MDP muramyl dipeptide

μg microgram

μm micrometer

μl microliter

NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells

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NOD2 nucleotide binding oligomerization domain containing 2

Nrl neural retina-specific leucine zipper protein

Nr2e3 nuclear receptor subfamily 2, group E, member3

% percent

P/PN postnatal day

PBS phosphate buffered saline

PCR polymerase chain reaction

PCNA proliferating cell nuclear antigen

Pias3 E3 SUMO-protein ligase PIAS3

PI3K-Akt PI-3 kinase

PKC protein kinase C

POAG primary open angle glaucoma

RA rheumatoid arthritis

SCFbTRCP Skp, Cullin, F-box containing complex, beta-transducin

repeat containing protein

SLE systemic lupus erythomatosus

SOCS3 suppressor of cytokine signaling 3

STAT signal transducers and activators of transcription

TAB TAK binding protein

TAK transforming growth factor β-activated kinase

TGF transforming growth factor

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TLR Toll-like receptor

Tnfaip3 tumor necrosis factor, alpha-induced protein

TNF tumor necrosis factor

TRADD tumor necrosis factor receptor type 1-associated DEATH

domain protein

TRAF TNFR-associated factor

TSS transcription start site

Ubc ubiquitin C

UBDs ubiquitin-binding domains

WT wild type

Znf4 zinc finger 4

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ACKNOWLEDGEMENTS

I would like to thank Dr. Zhang, Dr. Mclaughlin and Dr. Zagon for their help and support for

the past 3 years. I would not have gone so far without their care and trust.

I would like to thank my present and previous lab mates, Melissa Carol, Chris Siefring, Lucy

Lou, Weiyi Li and Jing Lu. They helped me through all the lab work, and taught me skills and

techniques crucial for my study.

I would also like to thank Dr. Barnstable and his lab crew, Evgenya Popova, Daniel Lapp,

Carolina Pinzon, Patrick Brown and Tiaosi Xing. They shared their experiences and equipment

with me to help me accomplish my experiments.

And all the thanks to my family and friends for their love and support throughout all these

years.

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CHAPTER 1

INTRODUCTION

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1.1. Developing retina is a great model to study central nerve system

1.1.1 Gross structures of retina

The retina of vertebrae animals is approximately 0.5mm in thickness and lines the inner

surface of the eye except the area where the optic nerve exists. This tissue is responsible for the

transformation of light input into electrical and chemical signals that are then transmitted to the

lateral geniculate nucleus, superior colliculus and other visual centers via the optic tract and

eventually projects to the visual cortex located in the occipital lobe. The retina is a layered

structure with output neurons (ganglion cells) adjacent to the lens and photoreceptors in the

outermost layer, which is adjacent to the pigment epithelium. The innermost layer of the retina

consists of photoreceptor neurons that are activated by light and specialize in converting

photonic signals into electrical signals. In humans and primates, sharp central vision is

dependent on the fovea, a circular region in the retina composed of layers of cone

photoreceptors without blood vessels. Interestingly, the fovea is not present in mice. Chicken

also have a rod-free central spot which is similar to the human fovea (Bruhn and Cepko, 1996).

1.1.2. Histological structures of retina

Murine retina contains ten distinct layers – three of which consist of neural cell bodies and

two of which consist of synapses. The retinal layers, in order of proximity to the lens are: inner

limiting membrane (ILM), nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer

(IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), external

limiting membrane (ELM), photoreceptor layer, and retinal pigment epithelium (RPE).

The ILM is composed of astrocytes and axon terminals of Müller cells. The basal lamina of

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ILM separates the retina from the vitreous cavity.

The NFL is composed mostly of axons of the ganglion cells in the GCL. The fibers course

horizontally, arch around the macula, and condense near the optic disc in the human eye.

Eventually, the fibers bend and pass through the sclera canal and bundle into the optic nerve.

The GCL consists of ganglion cell bodies and displaced amacrine cells. Dendrites of small

ganglion cells extend and arborize into the IPL while few larger ganglion cells ramify and extend

into the INL (Kolb et al., 1995). Dendrites of various cell types from the INL collectively form the

IPL. Also, dendrites of amacrine cells form synapses with the ganglion cells in GCL.

The INL is composed of closely packed amacrine cells, bipolar cells, and horizontal cells.

Bipolar cells are the most abundant and are found as two variants: rod bipolar cells and cone

bipolar cells. The inner processes of rod bipolar cells extend into the IPL and branch around the

cells in GCL; the outer processes reach into the OPL and end around the processes of rod

photoreceptors. Cone bipolar cell processes arborize into the IPL and contact with ganglion cell

dendrites. Horizontal cells are localized in the outer portion of the INL. Cell bodies of horizontal

cells are typically flat with horizontal axons that ramify in the same layer and dendrites that

branch and extend into the OPL. The amacrine cells are located in the inner portion of INL with

dendrites extending into the IPL (Kolb et al., 1995).

The OPL is a cluster of synapses between dendrites of horizontal cells from the INL and

axons of photoreceptors from the photoreceptor layer (Kolb et al., 1995).

The photoreceptor layer is the light detection layer of the retina that contains rod and cone

photoreceptors. Rod photoreceptor nuclei exhibit a cross-stripe appearance. They stack into

http://webvision.med.utah.edu/book/part-ii-anatomy-and-physiology-of-the-retina/inner-plexiform-laye/



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multiple levels throughout the layer, and are more abundant than cone photoreceptors in murine

eyes. The inner processes of rod photoreceptors extend into the OPL as an enlarged extremity,

and contact with the outer processes of rod bipolar cells. Cone photoreceptors have a stem-like

appearance, with a pyriform nucleus that fills the entire cell body. It is located adjacent to the

ELM. The thick inner processes of cone are extended into the OPL as a foot plate that contact

with the outer processes of cone bipolar cells (Kolb et al., 1995).

The ELM is adjacent to RPE and provides mechanical strength to maintain retinal structure.

This layer may also play an important role in the formation of the blood-retinal barrier (Omri et al.,

2010).

The ONL is also known as the photoreceptor layer – rods and cones in this layer are divided

into inner and outer segments. The outer segment of rod has a long cylindrical shape and

contains light-sensitive membranous discs that are embedded in the cell membrane. Cone, on

the other hand, has a shorter tapering outer segment with fewer discs. Since rod has more discs

than cone, it is more sensitive to light stimulation and plays a critical role in darkness and dim

light. In contrast, cone is more active in well-lit environment and is naturally the predominant

photoreceptor for color sensation. While rod contains rhodopsin and is sensitive to blue-green

light at 500nm, cones contain cone opsin and can be divided into three types: long-wavelength

cones that are sensitive to red light, medium-wavelength cone sensitive to green light, and

short-wavelength cone sensitive to blue light. Most mammalian species such as mice are

dichromatic, however, and can only sense light of medium and short wavelengths (Kolb et al.,

1995).


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1.1.3. Development of retina

The retina and the retinal pigment epithelium (RPE) are derived from the neural ectoderm

and are thus considered part of the central nervous system. Evagination of the diencephalon

becomes the optic vesicle, which interacts with the ectoderm and folds inward to form the

bilayered optic cup. The outer layer gives rise to the RPE, while the inner layer becomes the

retina. The optic cup is connected to the developing central nervous system by a stalk, which

differentiates into the glia of the optic nerve.

The development of the retina occurs in three steps. First, the correct number of cells of

each of the seven cell types is produced. Next, these cells migrate to their designated locations

and connect with other retinal neurons. Finally, synaptic refinement occurs to generate the neural

circuits. In general, the postmitotic progenitor cells from the ventricular zone of the optic vesicle

migrate to their respective layers, and extend dendrites and axons in directions guided by the

polarity of surrounding differentiating cells. Ganglion cells from the nerve fiber layer are the first

to differentiate, migrate, and send out axons that join with the optic nerve to reach the central

nervous system. Initially, the ganglion cells project dendrites through the entire IPL. Once these

dendrites are stratified and terminate with precision, amacrine cells then project dendrites in all

directions until they reach the border of IPL and INL. Immature bipolar cells project vertical

processes that terminate in the ILM and ELM, whereas the processes of mature bipolar cells

terminate precisely in the IPL and OPL. The pattern of horizontal cell processes alters from radial

during development to lateral by maturity. Dendrites and axons spread out to become the IPL

and OPL. Photoreceptor cells line the outer boundary of the retina, and attach to the dendrites of

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other cells.

Additionally, the retina raises its own glial cells, known as Müller cells, which is the major

supporting and homeostatic cells in the retina. It is believed that Müller cells, astrocytes from the

optical nerve, and microglial cells from the hematopoietic system together are responsible for the

major inflammatory response and immune defense in the retina.

1.2. Inflammation/immune response is associated with retinal pathogenesis

1.2.1 Diabetic retinopathy

Diabetes is one of the top incurable diseases in the world. Approximately 10% of the US

population suffers from diabetes, and nearly one-third of the diabetes patients develop some

degree of diabetic retinopathy (Yau et al., 2012). Diabetic retinopathy is the leading cause of

vision loss and blindness in working adults (Ciulla et al., 2003). Under normal conditions, the

retina maintains homeostasis – the blood vessels nurture the neural cells that produce factors to

strengthen the blood-retinal barrier and pro-survival neurotrophins equilibrate with inflammatory

mediators to maintain cell survival and function. Diabetes, however, can weaken the blood-retinal

barrier and allow blood-borne factors to invade the retina and cause neural damage through

chronic inflammation, in which proinflammatory factors override pro-survival neurotrophins and

the resulting neurodegeneration aggravates vascular damage. This neural-vascular dysfunction

progresses over time and ultimately leads to vision loss (Antonetti et al., 2006).

In humans, macular edema occurs during later stages of diabetic retinopathy without early

warning signs. For proliferative diabetic retinopathy, newly formed blood vessels bleed into the

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retina, leaving specks of blood or spots in the visual field, which causes blurry vision.

Non-proliferative diabetic retinopathy results in cotton wool spots, with abnormal vasculature and

superficial retinal hemorrhage. The vascular abnormalities in diabetic retinopathy may be caused

by accumulation of inflammatory molecules including cytokines, chemokines, complement and

other proinflammatory mediators, such as iNOS, COX2, and VEGF, that activate the NF-κB

pathway and alter vascular permeability and angiogenesis. Although each factor may influence

the retinopathy via a different mechanism, it is likely that innate immunity may play a role in the

pathogenesis of this disease (Tang and Kern., 2011).

Treatment for diabetic retinopathy is effective but not a cure. General treatment for macular

edema is scatter laser treatment, where hundreds of small lasers burn and stop the leakage in

the retina, and reduce excess fluid. If left untreated, diabetic retinopathy can cause severe vision

loss and even blindness.

1.2.2. Age-related macular degeneration (AMD)

AMD is the leading cause of vision loss among the elderly population. About two-thirds of the

elderly over 80 years old are affected by this disease (Friedman et al., 2004; de Jong., 2006).

AMD is a degenerative disease in the macula. In humans, the macula is a critical structure

responsible for central vision, fine detail, and image resolution. Pathological changes during

early AMD include yellowish deposits called drusen on the basal membrane of RPE cells.

Advanced AMD may be associated with poor central vision, retinal atrophy and choroidal

neovascularisation (CNV) (Johnson et al., 2011).

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Although AMD is incurable, current management includes the usage of anti-VEGF agents to

suppress CNV (Pieramici and Rabena., 2008), food therapy (Carpentier et al., 2009), and

support of adaptive devices. AMD is a multi-factorial disease. Aging is believed as one of the

causes of AMD, since aging slows the clearance of membrane debris results in the accumulation

of sub-RPE debris that may eventually form drusen (Johnson et al., 2011). Drusen contains

different protein and lipids synthesized either from the liver or locally by RPE cells (Hageman et

al., 2001; Ishida et al., 2004; An et al., 2006; Suuronen et al., 2007; Kim et al., 2009; Anderson et

al., 2010). Research in the past decades suggested that the activation of the complement system

may be involved in AMD pathogenesis and the formation of drusen (Anderson et al., 2010; Gehrs

et al., 2010; Hecker and Edwards., 2010). Involvement of the complement system is supported

by the detection of complement proteins in drusen, and the high risk of AMD development in

complement related gene mutation (Johnson et al., 2011; Degn et al., 2011).

Complement factor H (CFH) is the first identified AMD-associated gene (DeWan et al., 2004).

CFH is a crucial regulator of the alternative pathway in complement activation. Variation of CFH

on Y402H may affect ligand binding with C-reactive protein (CRP) and other acute phase

proteins, which suppress activation of the innate immune response (Perkins et al., 2010;

Khandhadia et al., 2011) and lead to increased inflammation within the macula.

Complement component 3 (C3) is also considered a key factor in the pathogenesis of AMD.

C3 can be cleaved into C3a and C3b, which further participate in the production of terminal

complex C5b-9. C3 and C3a are found in drusen (Mullins et al., 2000), as well as in CNV-affected

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retina after laser exposure (Nozaki et al., 2006). C3 gene deficient mice were resistant to CNV

development after laser exposure (Bora et al., 2005).

Another factor, single-nucleotide polymorphism rs11200638 in HTRA1, a serine protease, is

also suggested to affect the development of AMD (DeWan et al., 2006). Study by Yang and

colleagues provided evidence that HTRA1 expression is elevated in lymphocytes and RPE in

AMD patients (Yang et al., 2006). AMD patients with HTRA1 variants showed elevated

C-reactive protein level, suggesting that inflammation might contribute to AMD pathogenesis

(Yasuma et al., 2010).

1.2.3. Glaucoma

The second leading cause of blindness after cataract is glaucoma, a common disease

characterized by the slow, progressive degeneration of retinal ganglion cells (RGCs), optic nerve

axons (Kumarasamy et al., 2006) and retinal nerve fiber layer (Bodh et al., 2010). Risk factors for

glaucoma include elevation of intraocular pressure (IOP), hypertension, and cardiovascular

disease (Kumarasamy et al., 2006; Huang et al., 2009).

There are two types of glaucoma: open angle and close angle glaucoma. The most common

type of glaucoma is primary open angle glaucoma (POAG) (Margalit and Sadda., 2003). In

open/wide-angle glaucoma, fluid flow is reduced as a result of the degeneration and obstruction

of the trabecular meshwork, whose original function is to absorb the aqueous humor. Loss of the

aqueous humor absorption leads to increased resistance and thus a chronic, painless buildup of

pressure in the eye (Mozaffarieh et al., 2008). This alteration in aqueous absorption may be

related to the obstruction of inflammatory factors and debris at the filtering angle (Bodh et al.,

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2010).

A 67% increase and a 77% increase in cytokine receptors have been detected in normal

pressure glaucoma (NPG) patients and POAG patients, respectively, suggesting T-cell

over-activation in glaucomatous patients (Yang et al., 2001). Long-term presence of lymphocytes

and antigens from sustained neurodegeneration can lead to increased number of T-cells.

Cytokines are subsequently released, resulting in secondary antigen-mediated neurotoxicity

similar to that in autoimmune diseases (Kumarasamy et al., 2006).

Studies using Tenon’s capsule from glaucoma filtration surgery suggested an inhibition of

fibroblast proliferation in the Tenon’s capsule by IFN-alpha2b and IFN-gamma (Gillies et al., 1993;

Nguyen et al., 1994). IL1alpha and IL1beta stimulate the elevation of MMP3 expression in the

trabecular meshwork (Kelley et al., 2007), which affects the humor outflow (Huang et al., 2009).

Glaucoma patients exhibited high serum levels of sIL2R and IL10 (Yang et al., 2001; Yang et al.,

2007). POAG patients exhibit increased expression of IL4, IL12p40, and a reduced level of IL6,

IL23 and TNFa (Huang et al., 2009), suggesting an association between inflammatory activities

and glaucoma.

1.3. STAT3 is important for retinal development and retinal stress responses

1.3.1. Expression of STAT proteins in retina

It is well known that STAT proteins are essential for the development of the innate and

adaptive immunity in many organisms, and these proteins are the major mediators for cytokine

signaling (Darnell, 1997). The seven signaling transduction and activation of transcription

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proteins (STAT), including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 are

associated with cell metabolism and the signaling transduction of gene transcription. Each STAT

protein has a specific role that mediates the formation and development of mammalian eye.

During prenatal stages, expression of STAT1 was detected at embryonic day 12.5 (E12.5) in

the RPE layer. Expression of STAT2 was observed by E14.5. Expression of STAT3 was detected

in developing lens vesicle, lens fiber cells and nuclei, inner retina layer and retina progenitor cells

by E11.5, E12.5, and E18.5, respectively (Zhang et al., 2003). In the developing retina,

expression of STAT3 was first detected in the ganglion cell layer, followed by the inner nuclear

layer and the photoreceptor layer. When the retina maturation initiates at PN7, the expression of

STAT3 terminated, which suggests STAT3 is associated with initiation and progression of retina

differentiation. Expression of STAT4 was observed in the central region of the vitreal surface in

the retina by E12.5. Expression of STAT5a was also detected in the central region of the retina at

E12.5. This expression of STAT5a was found in the nucleus of cells localized in the inner retinal

layer, and the level of expression increased gradually as the retina developed. Expression of

STAT6 was detected by E12.5 in the inner retinal layer. The altered expression of STAT1, STAT3,

and STAT5a suggest these proteins are involved in RPE differentiation.

In adult retina, expression of STAT1 appeared in IPL and OPL, especially RPE, which

suggests STAT1 may involve in synaptic signaling transduction. Expression of STAT2 was weak

in INL, GCL, and RPE layers. Expression of STAT3 was observed in Müller cells, INL, GCL,

radial fibers, and RPE. STAT4 was weakly expressed in Müller cells. STAT5a was intensely

labeled in the nuclei of GCL, INL, and RPE, while STAT5b was expressed in the cytoplasm of

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GCL and RPE. STAT6 was labeled in INL, GCL and ONL with a punctuate appearance, and it is

also the only STAT protein clearly expressed in the non-pigmented epithelial layer of the ciliary

process (Zhang et al., 2003).

1.3.2. STAT3 is a signaling mediator for photoreceptor development

Disruption of STAT protein expression results in severe malfunction of both cellular and

humoral immunities in mice (Leonard and O’Shea, 1998; Takeda and Akira, 2000). For example,

IL12 induced Th1 cells were not observed in STAT4 knockout mice, and IL4 induced Th2 cells

were impaired in STAT6 knockout mice (Kaplan et al., 1996a, b; Shimoda et al., 1996; Thierfelder

et al., 1996).

Retinal progenitor cells are multipotent cells that can develop into different types of neural

retina cells in a conserved order. Both intrinsic and extrinsic factors may alter retinal

development through JAK-STAT signaling pathway, especially STAT3 signaling pathway

(Neophytou et al., 1997). Several known extrinsic molecules have been shown to promote rodent

rod development in vitro, including retinoic acid (Kelley et al., 1994), taurine (Altshuler et al.,

1993), basic fibroblast growth factor (bFGF) (Hicks and Courtois, 1992) and S-laminin (Hunter et

al., 1992). Other extrinsic factors have been suggested to inhibit rod development, including

transforming growth factor alpha (TGF) (Anchan et al., 1991; Lillien and Cepko, 1992), ciliary

neurotrophic factor (CNTF) (Kirsch et al., 1996) and leukemia inhibitory factor (LIF) (Ezzeddine

et al., 1997).

Other CNTF family members have the equivalent effect as CNTF on neural retina cells.

Except IL-6, the CNTF family members share a common receptor, which is gp130/LIFβ receptor,

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and they also share the same signaling pathway, which is mainly the STAT3 signaling pathway

(Zhang et al., 2004).

The critical role of STAT3 in CNTF-induced rod inhibition was concluded by the observation

that the expression of opsin was blocked by STAT3 dominant negative adenovirus, while the

expression of opsin was not inhibited by STAT1 dominant negative adenovirus. MAPK/ERK

pathway was also tested by culturing E17.5 retina with and without MAPK inhibitor PD98059 for

12 days. Opsin expression was not affected by the presence of PD98059, even in CNTF treated

group. Therefore, the CNTF-induced inhibitory effect is regulated by STAT3 not MAPK/ERK

signaling pathway (Zhang et al., 2004).

1.3.3. Cross-talk of PKC and STAT3 signaling in retina differentiation

CNTF also inhibit rod photoreceptor cell differentiation before rhodopsin expression by

activating the PI-3 kinase (PI3K)-AKT signaling pathway in rodents. Protein kinase C (PKC)

isoforms regulate cell physiology by phosphorylating different proteins in many cell types

(Pinzon-Guzman et al., 2011). PKC-beta1 and PKC-gamma are essential for rod photoreceptor

differentiation in mouse retinas. PMA and IGF1 induce rod differentiation in a PKC-dependent

manner days before rod development in untreated explants, which is defined by the expression

of opsin and Crx,.

During later stages of development, PKC-beta1 and PKC-gamma co-localized with

progenitor cells that are PCNA and STAT3-positive. Application of PKC inhibitors of either

isoform resulted in partial reduction of rods, and knockout of both isoforms resulted in complete

absence of rods. Furthermore, activation of PKC reduces STAT3 phosphorylation. In contrast,

14

inhibition of PKC result in increased phosphorylation of STAT3 and delayed cell cycle exit. In

adult retinas, IGF1 activates PI3K-AKT signaling pathway, while in neonatal retinas, IGF1

functions as a PI3K inhibitor. In all, specific PKC isoforms regulate rod differentiation through

PI3K-AKT signaling pathway and control STAT3 phosphorylation (Pinzon-Guzman et al., 2011).

1.3.4. STAT3 mediates stress responses in retina

In mature retina, CNTF activates the JAK-STAT pathway in neural retina and glia cells as a

self-protective mechanism against environmental stress stimuli and injuries. Peterson and

colleague studied the STAT1, STAT3 and MAPK/ERK pathways after CNTF stimulation

(Peterson et al., 2000). Results showed that phosphorylation of STAT3 initiated 15min after

intra-vitreal injection with Axokine (a CNTF analog, AXK) and terminated by day 4. The total

expression of STAT3 increased from 16h to 2d of treatment, while the phosphorylation of STAT3

in vehicle-treated group is only slightly activated. Small amount of STAT1 phosphorylation is

detected from 16h to 2d of treatment, and the total phosphorylation of STAT1 has a distinct

increase, which persisted for 7 days.

In the same study, a robust expression of MAPK activation was observed 60min after AXK

treatment, and the expression significantly decreased by day 4. Their study also located the

source of STAT and MAPK activation within the retina. Vehicle treatment exhibits no STAT3

activation, while AXK treated group showed STAT3 activation at NFL and GCL. The region near

the injection site has the most expression, while far injection site exhibited much weaker

expression.

A robust expression of phosphorylated STAT3 was detected at NFL and INL 15min after AXK

15

treatment. The expression gradually extends and stopped at the outer limiting membrane. The

expression of MAPK and phosphorylated MAPK revealed the similar pattern at INL, NFL as well

as processes within IPL and OPL to the outer limiting membrane after AXK injection. These

results all suggested that STAT3 and MAPK are activated by CNTF, meanwhile the total amount

of expression of STAT3 and STAT1 did not alter. Furthermore, expression of GFAP was detected

in rat retinas at NFL, INL and IPL, which indicate that activation of STAT3 occurred in neurons

and glia cells. Stress stimuli for instance bright light damage affects the expression STAT1 and

STAT3. With up to 48h of bright light exposure, expression of STAT3 and STAT1 are activated

and up-regulated. Anesthesia can also cause stress stimulation. Treatment with xylazine, not

ketamine at different time points showed expression of STAT3 4h after stimulation. Mechanical

injury produced by placing a 30Gl needle into sclera showed a positive GFAP and STAT3

expression at the injury site, whereas distal region remain the same as untreated (Peterson et al.,

2000).

STAT3 has been considered as an anti-inflammation factor. Recent studies revealed that

STAT3 is tightly associated with the regulation of innate immunity in both immune and

non-immune cells. Deletion of STAT3 in hematopoietic system such as in bone marrow lead to a

Crohn’s disease-like pathogenesis along with an abnormal innate response (Welte et al., 2003),

including increase production of Th1 cytokines and reduction of macrophage phagocytosis

(Carroll and Zhang, in preparation). Deficiency of STAT3 in cardiomyocytes (Jacoby et al., 2003),

endothelial cells (Kano et al., 2003; Zhang et al., 2006), hepatocytes (Moh et al., 2007), and

astrocytes (Zhang et al., in preparation) all revealed elevated production of Th1 cytokines. These

16

results suggest that the regulation of STAT3 protects cells from immunological damages.

1.4. NF-κB, the master control for inflammatory and immune responses

1.4.1. Basics of NF-κB

NF-κB is a transcription factor that regulates the expression of an exceptionally large

number of genes in response to infection and inflammation. These genes include interleukin-1β

(IL1β), tumor necrosis factor-α (TNFα), bacterial lipopolysaccharide (LPS) and antigenic

peptides (Shembade and Harhaj., 2012). NF-κB is also activated in stressful situations requiring

rapid reprogramming of gene expression (Hyden and Ghosh, 2008). The five members of the

mammalian NF-κB family, p65 (RelA), RelB, c-Rel, p50/p105 (NF-κB1), and p52/p100 (NF-κB2),

exist in unstimulated cells as homo- or heterodimers bound to IκB family proteins (Hayden and

Ghosh, 2004). NF-κB subunits each contains an approximately 300-amino-acid domain located

in the amino (N)-terminus known as the Rel homology domain. The Rel homology domain

confers DNA binding, nuclear localization and dimerization of NF-κB proteins (Shembade and

Harhaj, 2012).

1.4.2. NF-κB mediated signaling

NF-κB activation can be proceed by two distinct signaling cascades. Canonical NF-κB

signaling is induced in response to pro-inflammatory cytokines such as tumor necrosis factor

(TNF) and microbial infection, and mainly induces the expression of pro-inflammatory and

survival genes. Whereas non-canonical NF-κB signaling is initiated by stimulation of cell

differentiating or developing stimuli such as lymphotoxin β, and mainly regulates the

17

development of lymphoid organs and adaptive immune responses (Renner and Schmitz, 2009).

In the canonical pathway, NF-κB is expressed in virtually all cell types and is activated by diverse

stimuli ranging from stress, radiation, cytokines, bacterial and viral products to antigens. NF-κB

complexes are sequestered in the cytoplasm in un-stimulated cells by inhibitory regulator of

NF-κB proteins (IκB) that all share a series of ankyrin repeat domains (Hayden and Ghosh, 2004;

Hinz et al., 2012).

Upon stimulating with a wide variety of agonists, including TNF, interleukin (IL)-1 and toll-like

receptor (TLR) ligands, IκBα is phosphorylated on serine32 and 36 residues by a multi-subunit

kinase complex, IκB kinase (IKK) which consists of two catalytic subunits (IKKa and IKKb) and a

regulatory subunit (IKKc or NEMO) (Hacker and Karin, 2006; Liu et al., 2012). The E3 ubiquitin

ligase complex recognizes phosphorylated IκBα (Spencer et al., 1999; Kanarek et al., 2012),

subsequently polyubiquitinate IκBα and eventually degrades by the proteasomes. The

ubiquinated IκBα releases NF-κB, which then accumulates in the nucleus and activates

transcription of its target genes (Vereecke et al., 2009). As an NF-κB target gene, IκBα functions

as the terminator of negative feedback process in NF-κB signaling pathway (Sun et al., 1993).

The activation of NF-κB signals must be tightly monitored to avoid excessive chronic

inflammatory responses which may harm the host (Shembade and Harhaj, 2012). Defects in the

regulation of NF-κB-dependent gene expression contribute to a variety of diseases, including

inflammatory and autoimmune diseases, neurological disorders and cancer (Vereecke et al.,

2011).

1.4.3. Regulation of NF-κB signaling

18

The NF-κB signaling cascade is prominently regulated by ubiquitylation, a process that can

generate series of post-translational modifications that direct proteins towards distinct biological

fates (Pickart and Eddins, 2004). Ubiquitin is a 76 amino acid polypeptide that is covalently

attached to lysine residues on protein substrates (Wilkinson et al., 1980). It either triggers

proteasomal degradation, protein trafficking, signal transduction or the DNA damage response

(Shembade and Harhaj, 2012). Three classes of proteins are involved in the unbiquitiation

process: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes，and E3 ubiquitin

ligases (Hershko and Ciechanover, 1998). Adenosine triphosphate (ATP)-dependent E1 enzyme

activates ubiquitin, then E1 enzyme transfers the activated ubiquitin to the active site of an E2

ubiquitin-conjugating enzyme which forms an E2-ubiquitin thioester linkage. Finally, an E3

ubiquitin ligase combines the activated ubiquitin to a protein substrate by linking the C-terminal

glycine of ubiquitin to the lysine residue of the protein (Harhaj and Dixit, 2012). The E3 ligase is

thought to confer specificity to ubiquitination and directly contacts the substrate (Shembade and

Harhaj, 2012). There are seven potential lysine (K6, K11, K27, K29, K33, K48 and K63) residues

in ubiquitin that may participate in chain linkage formation (Ikeda and Dikic, 2008). Linear

polyubiquitination has emerged as an important regulator of NF-κB activation by multiple stimuli

(Tokunaga et al., 2009). K48-linked polyubiquitin chains are recognized by the 26S proteasome

and trigger the degradation of the protein substrate (Hershko and Ciechanover, 1998).

K63-linked polyubiquitin chains typically do not trigger protein degradation but instead regulate

non-proteolytic functions including protein trafficking, kinase activation, DNA damage response

and signal transduction (Mukhopadhyay and Riezman, 2007).

19

In the TNFR pathway, TNF serves as a potent activator of NF-κB which binds to the TNF

receptor (TNFR), leading to receptor trimerization and the recruitment of adapter molecules

TNFR associated death domain (TRADD), receptor-interacting protein 1 (RIP1), the E3 ubiquitin

ligases TNFR-associated factor 2 (TRAF2), TRAF5, cellular inhibitor of apoptosis 1 ⁄ 2 (cIAP1 ⁄ 2),

and LUBAC (Wertz and Dixit, 2008; Haas et al., 2009). TRADD serves as a platform for binding

to the adaptor molecule RIP1 and the E3 ligases TRAF2, cIAP1/2 and LUBAC (Wertz and Dixit,

2008). RIP1 ubiquitination likely functions as a molecular scaffold to recruit proteins bearing

ubiquitin-binding domains (UBDs) (Kanayama et al., 2004). The IKK complex is recruited to RIP1

via NEMO binding to RIP1 polyubiquitin chains (Ea et al., 2006). The ubiquitin binding adaptors

TAB2/TAB3 and NEMO recruit the TAK1 and IKK, respectively, to the ubiquitinated RIP1 to

enable TAK1 phosphorylation, and hence activation of IKKβ (Wang et al., 2001; Kanayama et al.,

2004; Ea et al., 2006).

Similarly, IL-1R/TLR4 pathway activates NF-κB in the same mechanism. The adapter

molecule myeloid differentiation factor 88 (Myd88) recruits kinases of the IL1 receptor-associated

kinase (IRAK) family (IRAK1 and IRAK4) to the receptor complex, which triggers the

oligomerization and activation of the E3 ubiquitin ligase TRAF6 (Liu and Chen, 2000). TRAF6

undergoes K63-linked autoubiquitination and provide a platform to recruit TAK1 activation and

phosphorylates IKK kinases through binding to TAB2/3 and NEMO, respectively (Akira S, 2003).

TAK1 is subsequently activated and triggers IKK/NF-κB and mitogen-activated protein

kinase/c-Jun N-terminal kinase activation (Jiang et al., 2002).

Deubiquitinases (DUBs) are proteases that cleave ubiquitin from target proteins and

20

therefore oppose the function of E3 ligases (Harhaj and Dixit, 2012). It cleaves ubiquitin from

proteins that are modified post-translationally to either rescue protein degradation by removal of

K48-linked chains or modulate signaling or trafficking by removal of K63-linked chains

(Reyes-Turcu et al., 2009). The cleaved ubiquitin molecules may be recycled for additional

ubiquitination events, thus contributing to ubiquitin homeostasis (Reyes-Turcu et al., 2009).

DUBs may also modify the ubiquitin chains by changing the number of ubiquitins or by altering

the traditional K63 linkage to K48 linkage (Wertz et al., 2004).

The two most well studied DUBs that regulate NF-κB are cylindromatosis (CYLD) and

Tnfaip3/A20 (Harhaj and Dixit, 2011). Both CYLD and Tnfaip3/A20 are important negative

feedback regulators for homeostatic control of NF-κB and inflammation responses (Shembade

and Harhaj, 2012). My study is specifically on Tnfaip3/A20 in this project.

1.5. Negative regulation of NF-κB signaling

1.5.1. Tnfaip3/A20 is a specific ubiquitinases of the NF-κB signaling pathway

Tnfaip3/A20 is a cytoplasmic zinc finger protein (Coornaert et al., 2009). It is originally

characterized as an inhibitor of TNF-induced cell death (Opipari et al., 1992). Recent studies are

all focused on its negative feedback regulation in the NF-κB activation. A20 is regulated at both

the transcriptional and the post-transcriptional level (Ma and Malynn, 2012). In most cell types,

basal A20 expression is quiescent but can be rapidly induced upon stimulation.

Tnfaip3/A20 functions as a negative feedback regulator of NF-κB signaling pathway once

activated by stimuli (Vereecke et al., 2009). In most cases, the activation of NF-κB is transient

21

and cyclic upon continuous stimulation, which is due to specific negative feedback control

systems such as the NF-κB-inducible synthesis of IκB and Tnfaip3/A20 proteins (Coornaert et al.,

2009). The physiological importance of Tnfaip3/A20 as an anti-inflammatory protein is clearly

demonstrated by the phenotype of Tnfaip3/A20-deficient mice, which are cachexic and develop

severe multi-organ inflammation causing premature lethality (Lee et al., 2000).

Tnfaip3/A20-deficient MEFs and thymocytes also exhibit a prolonged activation of NF-κB after

administration of TNF (Coornaert et al., 2009).

1.5.2. Tnfaip3/A20 is an universal inhibitor of the NF-κB signaling pathway upon

stimulation by various activators

Despite its important role in inflammation, Tnfaip3/A20 is required for terminating NF-κB

signaling in response to microbial products such as lipopolysaccharide (LPS) and muramyl

dipeptide (MDP) (Hitotsumatsu et al., 2008), which trigger TLR4 and Nucleotide binding

Oligomerization Domain containing 2 (NOD2) receptors, respectively. Deregulated TLR signaling

in response to commensal bacteria was shown to be responsible for the multi-organ

inflammation and premature death of Tnfaip3/A20 knockout mice (Turner et al.,

2008).Tnfaip3/A20 may target upstream receptor molecules such as E3 ligase TRAF2 to

regulate TRAF2-induced NF-κB activation (Song et al., 1996; Shembade and Harhaj, 2012).

Tnfaip3/A20 may also inhibit NF-κB activation by triggering overexpression of RIP1 (Heyninicj et

al., 1999).

In the TNFR pathway, the K63-linked polyubiquitin chains of RIP1 are cleaved by

Tnfaip3/A20, and then K48-linked chains catalyses via the fourth zinc finger (ZnF4) to trigger the

22

proteasomal degradation of RIP1 (Wertz et al., 2004).

In the IL-1R\TLR4 pathways, Tnfaip3/A20 either targets the E3 ligase TRAF6 to inhibit

IL-1-induced NF-κB activation (Heyninck and Beyaert, 1999), or it inhibits NF-κB activation

through binding E3 ligases TRAF6, TRAF2 and cIAP1/2 with E2 enzymes Ubc13 and UbcH5c,

and triggers the ubiquination and degradation of E2 enzymes. It does not trigger RIP1

degradation as in the TNR pathway (Mattera et al., 2006; Shembade et al., 2010; Shembade and

Harhaj, 2012).

1.5.3. Loss of NF-κB negative feedback and human diseases

In most cell types, Tnfaip3/A20 is inducible by proinflammatory cytokines or mitogens and

inhibits NF-κB activation in a negative feedback loop (Harhaj and Dixit, 2012). Recent studies

have developed Tnfaip3/A20 alleles conditional knockout mice (Tnfaip3 flox/flox mice), which

enabled lineage-specific deletions of Tnfaip3/A20 for studies on Tnfaip3/A20 functions in specific

immune cell types (Ma and Malynn, 2012).

Deletion of Tnfaip3/A20 in dendritic cells (DCs) and myeloid cells is associated with the

development of autoimmune diseases (Shembade and Harhaj, 2012). Mice lacking Tnfaip3/A20

in DCs (Tnfaip3fl/flCD11c-Cre) did not develop severe multi-organ inflammation observed in

Tnfaip3/A20 deficient mice, but rather exhibited splenomegaly, lymphadenopathy and

auto-immune diseases such as colitis and spondyloarthritis (Hammer et al., 2011). In

Tnfaip3flox/flox Cd11c-Cre mice, Tnfaip3/A20-deficient DCs are highly activated and exhibit

excessive production of pro-inflammatory cytokines (Ma and Malynn, 2012).

Macrophage, which shares the immune-stimulatory functions with DC, also develops

23

autoimmune disease when Tnfaip3/A20 is deleted. Mice with Tnfaip3/A20 deletion in the myeloid

cells (Tnfaip3fl/flLysM-Cre) exhibited elevated production of TNF, IL-1β, IL-6 and MCP-1

(Matmati et al., 2011). This increased activation of inflammatory cytokines is also detected in joint

tissue, which supports the observation in erosive polyarthritis, which is driven by

Tnfaip3/A20-deficient myeloid cells via IL-6-and TLR4-dependent signals (Ma et al., 2012).

Inflammatory bowel disease (IBD), Crohn’s disease (CD) in specific, is suggested as the

result of dysregulated homeostasis in the host immune system (Strober et al., 2002;

Rakoff-Nahoum et al., 2004). Mice genetically deficient in Tnfaip3/A20 also develop severe

intestinal inflammation (Lee et al., 2000). Intestinal epithelial cells with Tnfaip3/A20 deficiency

were more sensitive to TNF-induced apoptosis, causing intestinal barrier dysfunction,

commensal microflora infiltration and inflammatory responses (Vereecke et al., 2010). Thus,

Tnfaip3/A20 is a major anti-apoptotic protein in intestinal epithelial cells which maintains

epithelial barrier integrity and homeostasis.

Other autoimmune diseases including systemic lupus erythomatosus (SLE), rheumatoid

arthritis (RA), psoriasis, Type 1 diabetes, and cancer are also associated with Tnfaip3/A20

variations. It has been suggested that an SLE-associated Tnfaip3/A20 variant within the DUB

domain of Tnfaip3/A20 (Phe127Cys) weakens NF-κB inhibition compared to wild-type

Tnfaip3/A20 (Musone et al., 2008). TNF is the major pro-inflammatory cytokine regulator in RA.

Two variants were suggested to influence Tnfaip3/A20 (150kb downstream of A20) by the

presence of potential regulatory DNA elements in this region (Vereecke et al., 2009). Further

fine-mapping studies also supported the association of the polymorphisms in Tnfaip3/A20 and

24

the intergenic region in the variants with RA (Dieguez-Gonzalez et al., 2009; Orozco et al., 2009).

These findings all suggested Tnfaip3/A20 as a likely candidate for RA (Vereecke et al., 2009).

In all, Tnfaip3/A20 plays an important role in mediating the negative feedback regulation of

NF-κB signaling pathway. Without the regulation of Tnfaip3/A20, proinflammatory responses will

override the homeostasis of the immune system, which eventually contribute to development of

autoimmune diseases including IBD, SLE and RA. However, Tnfaip3/A20 has never been

studied in neural system including the retina. My study here provides the first outline of

Tnfaip3/A20 in the retina.

1.6. Summary

The retina is an immune privilege site. Recently, growing evidence suggest that chronic

inflammation and immune activation are strongly associated with human retina diseases. Under

normal conditions, healthy retina maintains homeostasis. When stimulated, elevated immune

response activates JAK-STAT, NF-κB, and PI3K-AKT pathways via cytokines, endotoxins, and

immune-tolerance signaling pathways. As an important negative regulator of the NF-κB pathway,

Tnfaip3/A20 could mediate the equilibrium of immune responses in the retina. Therefore, it is

crucial to study the potential gene regulation of inflammatory and immune activated molecules

including Tnfaip3/A20 during retinal homeostasis to gain a better understanding of the immune

responses in the retina.

25

CHAPTER 2

OBJECTIVES

26

2.1. Overall hypothesis

Association between multiple retinal diseases and inflammatory and innate immune

responses has been described in the literature. These responses are conducted via extracellular

signaling and intracellular signaling –extracellular signaling is triggered by the binding of ligands,

such as cytokines, endotoxins, and immune-tolerance proteins, to cytokine receptors and toll-like

receptors, which then activate the intracellular JAK-STAT, NF-κB and PI3K-AKT pathways. We

hypothesize that genes involved in this process have the potential to be expressed in the mouse

retina. ChIP-Seq analysis is a powerful tool to study gene transcriptional accessibility

genome-wide. By examining methylation of histone 3 lysine 4 (H3K4) and histone 3 lysine 27

(H3K27) at gene transcriptional start sites we can determine the relative transcriptional

accessibility for each gene. Recently, a genome-wide epigenetic mapping study in mouse retina

and its database has become available (Popova et al., 2012), allowing us to acquire information

on transcriptional accessibility for all genes related to inflammatory/immune responses.

The overarching goal of this study is to determine whether genes corresponding to

inflammation and immune responses are transcriptionally accessible in mouse retina. We

propose to investigate the expression and regulation of Tnfaip3/A20 during retinal development.

2.2. Specific Aim 1: Epigenetic analysis on extracellular signaling of

inflammatory/immune response genes during retina development

ChIP-Seq data of several endotoxins, cytokines, and immune-tolerance related genes

expressed in the retina were categorized and analyzed by cluster and tree analysis.

27

2.3. Specific Aim 2: Epigenetic analysis on intracellular signaling of inflammatory/immune

response genes during retina development

ChIP-Seq data of PI3K-AKT, JAK-STAT and NF-κB related genes expressed in the retina

were categorized and analyzed by cluster and tree analysis.

2.4. Specific Aim 3: Examination of NF-κB negative feedback signaling in retina

The in vivo expression levels of Tnfaip3/A20, Trafd1, and Pcbp2 were analyzed via RT-PCR.

Samples were treated with LPS stimulation and collected at various time points.

28

CHAPTER 3

METHODS AND MATERIALS

29

3.1. Animals

All procedures were approved by Institutional Animal Care and Use Committees (IACUC) at

Penn State Hershey. Mouse strains from C57BL/6j and BALB/cj backgrounds used in this study

were bred in the animal facility of Penn State College of Medicine. Mice were housed in standard

cages with 12h light/12h dark cycle. Rodent chows were given, as well as water ad libitum.

3.2. Tissue collection

3.2.1. Retina evisceration

Dissect out the eyes from the mouse. Place all the eyes in fresh PBS. Use a curved forceps

(CAT#5/45, DUMONT) to hold the globe at the optic nerve head. Use another curved forceps to

pull off the optic nerve, revealing a lumen without retina. Insert the tip of one forceps into the

lumen, then insert another forceps, and gently tear the globe apart. Peel over the sclera, and turn

the eye inside out. Gently peel off the retina, and remove the vitreous, as well as any other

structure attached. The retina should reveal as a pinkish, vascularized tissue.

3.2.2. Spleen isolation

Cut an incision at the lower left of its back. Expose the spleen, which is a dark red, elongated

tissue. Gently lift the spleen up, cut away the connective tissue to release the spleen from the

animal. One fourth of the spleen will be used for RNA extraction, while the rest is wrapped with

foil and frozen for future use.

3.3. LPS treatment

30

Lipopolysaccharides (LPS) from Escherichia coli 055:B5 (CAT# F8666-5MG) was

purchased from Sigma-Aldrich. LPS was diluted in a stocking solution of 1ug/ul. A working

concentration of 0.5ug/ul was used to treat retina explants, while 1ug/ul in 200ul solution was

used for mouse intra-peritoneal (IP) injection.

3.4. Retina explants culture

Retina explant culture followed protocols from previous study (Zhang et al., 2002).Similar to

general retina evisceration, retina for explants culture needs to be completely sterilized.

Therefore, the eyes need to be sterilized with 70% ethanol spray before transferring into

sterilized PBS. The forceps must be sterilized with 70% ethanol before use. 1ml of

UltraCULTURE medium (CAT# 12-725F, Lonza) is used as culture medium for retina explants.

3.5. RNA extraction and purification

RNA extraction and purification followed the manufacturer’s protocol from RNeasy Mini Kit

(50) (CAT#74104, Qiagen). β-Mercaptoethanol (β-ME) was added to Buffer RLT before use, in a

ratio of 10ulβ-ME per 1ml Buffer RLT. 4 volumes of 96-100% ethanol was added to Buffer RPE

before using for the first time. Retina/ spleen samples were excised from the mice (two adult

retinas per unit or one fourth of the spleen per unit). Disrupt the tissue with autoclaved pestle and

homogenize the lysate in 500ul of Buffer RLT. Add 1 volume of 70% ethanol to the lysate, mix

and pipette thoroughly. Transfer 500ul of sample including any precipitate into an RNeasy spin

column placed in a 2ml collection tube. Close the lid tightly, and centrifuge at ≥10,000rpm for at

31

least 15s. Discard flow through. Repeat this step until the samples are all filtered. Add 700ul of

Buffer RW1 to the spin column. Close the lid tightly, and centrifuge at ≥10,000 rpm for at least

15s. Discard flow through. Add 500ul Buffer RPE to the spin column. Close the lid and centrifuge

at ≥10,000rpm for at least 15secs. Discard flow through. Add another 500ul of Buffer RPE to the

spin column, close the lid and centrifuge at ≥10,000rpm for 2min to wash the spin column

membrane. Discard flow through. Place the RNeasy spin column in a new 2ml collection tube,

discard old collection tube with flow-through. Close the lid and centrifuge at full speed for 1min.

Place the RNeasy spin column in a new 1.5ml collection tube. Add 30ul of RNase-free water.

Close the lid and incubate for 10min at room temperature. Centrifuge at ≥10,000rpm for 1min to

elute the RNA.

3.6. Spectrophotometry

RNA concentration was measured with the light spectrophotometer Genespec II. The

wavelength was set between 220-340nm. The optical density (OD) at 260nm was used for

calculation.

3.7. RNA reverse transcription

RNA reverse transcription followed the manufactory protocol (Superscript III, Invitrogen Life

Technologies). SuperScript® III First-Strand Synthesis System (CAT# 18080-051) was

purchased from Invitrogen Life Technologies. RNA samples and all reagents (including

DEPC-treated water, 10mM dNTP mix, Random hexamers, 10X RT buffer, 25mM MgCl2 and

32

0.1M DTT) were mixed and centrifuged before use. Each reaction contains 50ng/ul of RNA, 1ul

of 10Mm dNTP mix, 1ul of Random hexamers, and DEPC-treated water to make a total volume

of 10ul. The RNA/primer mixture was incubated at 65°C for 5mins, then kept on ice for 1 min. A

2X reaction mix was prepared in a separate tube in the indicated order, including 2ul of 10X RT

buffer, 4ul of 25mM MgCl2, 2ul of 0.1M DTT and 1ul of RNaseOUT (40U/ul) for one reaction. A

0.3 reaction is added to compensate the reagent loss during handling. 9ul of 2X reaction mix was

added to each incubated RNA/primer mixture, and kept at room temperature (~25°C) for 2

minutes. Add 1ul of Superscript III reagent to each RNA/primer mixture from previous step, and

incubate at room temperature for 10mins, then at 42°C for 50mins, followed by 15mins at 70°C.

Chill on ice. Add 1ul of RNase H to each reaction tube, incubate for 20mins at 70°C, then the

reaction can be used immediately or stored at -20°C.

3.8. Primer design and synthesis

A program Primer-BLAST from NCBI was used for all primer design. Primers were

customized and purchased from Integrated DNA Technologies (IDT, www.idtdna.com). The

sequence information and primer melting temperatures are listed below (Table 1):

Table 1, Primer information

Primer sequence Product

size (bp)

Annealing

temperature

mB-Actin_F 5′- TGTTACCAACTGGGACGACA-3′

mB-Actin_R 5′- GGGGTGTTGAAGGTCTCAAA-3′

165 56

mTnfaip3P1_F 5′-TGCAATGAAGTGCAGGAGTC-3′ 200 56

http://www.idtdna.com/

33

mTnfaip3P1_R 5′-TGGGCTCTGCTGTAGTCCTT-3′

mPcbp2-AS_F 5′-CCCTACCAGGCACCAAGATA-3′

mPcbp2-AS_R 5′-GGTTTCTCAGGTGGCAATGT-3′

151 58

mPcbp2-NT_F 5′-TCCAGCTCCCTGTAACTGCT-3′

mPcbp2-NT_R 5′-TTAGTCGGTCCAGCCAAAGT-3′

221 56

mTrafd1_F 5′-AGTCTGTGCCTGAGGCTGAT-3′

mTrafd1_R 5′-GAGAAGGGTTGCAGCTTGTC-3′

156 58

mTnfaip3P2_F: 5'-CTAACGGAATGGGCTTTACC-3'

mTnfaip3P2_R: 5'-TGCATGCATGAGGCAGTTTC-3'

369 58

3.9. PCR

The routine PCR protocol was used from Zhang Lab. The PCR mix include dNTP Master Mix

(CAT# CB4421-2, Denville Scientific), double distilled water, GT buffer (100mM KCl (CAT#

P4504, Sigma Alderich), 40mM Tris-HCl (CAT# 4103-01, JT Backer), 6mM MgCl2 (CAT#

2444-01, JT Backer)), Choice-Taq™ DNA Polymerase CAT# CB4050-2, Denville Scientific) and

proper primers. The reaction cycle starts with a denature temperature at 95°C for 45secs,

followed by an annealing temperature at 55°C or higher for 45secs depending on the melting

temperature of the primers. Finally the complementary copy of desired DNA strand is produced

at 72°C for another 45secs. Addition to the cycle, a 3mins denature step at 95°C is placed before

the cycle, as well as a 10mins extension step at 72°C after the cycle. The cycle for RT-PCR

reduced to 23-28 cycles and the details are shown in Figure 1. The gel (CAT# 16500500,

Invitrogen Life Technologies) used for RT-PCR is 2%. Gel boxes were purchased from Bio-Rad.

34

Figure 1. PCR Scheme. The reaction starts from the left: step 1, 95°C for 3mins; step2, 95°C for

45secs, 55°C or higher for 45secs, 72°C for 45secs, cycle 23-28 times; step 3, 72°C for 10mins,

then proceed infinitely at 4°C.

3.10. ChIP-Seq database and data collection

ChIP-Seq database were collected from GEO data repository (GSE38500, Popova et al., 2012)

and visualized in UCSC Genome Browser (www.genome.ucsc.edu) for epigenetic mapping.

3.11. Cluster analysis

Hierarchical cluster analysis was performed through Gene Cluster 3.0 (Eisen et al., 1998).

25,158 genes were pre-categorized by their functions. Then genes of each categorized group

were classified into two clusters through average linkage depending on their H3K4me2 and

35

H3K27me3 accumulation. Tree analysis was done via Java Tree View (version 1.1.6r2) for

visualization.

3.12. Image J and densitometry analysis

For quantitative analysis, the intensity of RT-PCR band was analyzed via Image J (version

1.46r). Background correction was set at a default value of 50. Density of bands was measured

by pixels.

3.13. Statistical analysis

Statistical analysis was performed via SPSS 3.0. Student t-test (unpaired) was used to

compare density of each sample to its beta-actin control bands. Samples from different groups

were analyzed through one-way ANOVA at different time points. P< or= 0.05 are considered as

significant differences.

36

CHAPTER 4

RESULTS

37

4.1. Epigenetic analysis of extracellular signaling genes of inflammatory/immune

response during retina development

4.1.1. Introduction

Epigenetic markers or posttranslational histone modifications associated with certain

genomic positions such as transcriptional start sites (TSS) indicate the status of transcriptional

accessibility of genes. Histone 3 lysine 4 methylation (H3K4me) at the TSS has been well

characterized as an active status of gene transcription. In contrast, Histone 3 lysine 27

methylation (H3K27me) at the TSS regions corresponds to a repressive status of gene

transcription. Using ChIP-Seq techniques, our previous study showed that H3K4me2 and

H3K27me3 can be used to distinguish cell type specific genes and specific immune response

signaling molecule transcription during retinogenesis (Popova et al., 2012). Using this published

database, we are able to specify extracellular signaling of immune related genes and analyze

their status of histone modification during retina development. For this specific Aim, we focused

on the genes associated with extracellular signaling of inflammatory/immune responses.

4.1.2. Collection of genes

In this study, we focused on interleukin/ interleukin receptors, complements and genes in the

toll-like receptor family collected from the database (GEO# GSE38500) our group have

published previously (Popova et al., 2012) and ENCODE/LICR Histone Mods by ChIP-Seq

analysis.

4.1.3. Epigenetic analysis

4.1.3.1. Cluster analysis of interleukin ligands and their receptors

38

We have selected and analyzed several interleukin/interleukin receptor genes and their

isoforms as examples and categorized them into two clusters. Cluster 1 was classified according

to the degree of H3K4me2 accumulation (Figure 2). 70% of the genes in cluster 1 are interleukin

receptor related, including Ifnar1, Ifnar2, Il11ra, Il1rap, Il3ra, Il17rd, Il10rb, and Il4ra, whereas 30%

of the genes are interleukin related, including Il17d, Il6st, Il7, Il15, and Il1f5 (Figure 3). The higher

percentage of interleukin receptors (Ilr) in cluster 1 indicates that a larger number of Ilrs are

transcriptionally accessible compared to interleukins. Cluster 2 did not exhibit the same distinct

pattern as cluster 1. Of the 104 genes in cluster 2, 45% of the genes are interleukin receptors,

while 55% of the genes are interleukins.

39

40

Figure 2. Cluster analysis of H3K4me2 and H3K27me3 occupancy at different

developmental stages for interleukin and interleukin receptors. The tree-view shows the

expression of interleukin and interleukin receptor genes on E17.5, PN1, PN7 and PN15. These

genes were divided into two clusters (C1-C2) according to their H3K4me2 accumulation and/or

H3K27me3 accumulation. The level of accumulation depends on the redness of the correlated

block. Black represents absence of accumulation.

Figure 3. Bar chart of interleukins and interleukin receptors occupancy in cluster 1 and

cluster 2. The percentages of interleukins/ interleukin receptor genes are compared in the two

clusters. The shaded bar represents percentage of interleukins, and un-shaded bar represents

interleukin receptors.

41

4.1.3.2. Cluster analysis of complements

We performed hierarchical cluster analysis as described previously for all complement

genes from the RefSeq database. Genes in cluster 1 exhibit higher H3K4me2 accumulation

compared to H3K27me3 accumulation (Figure 4). In contrast, genes in cluster 2 exhibit lower

H3K4me2 accumulation compared to H3K27me3 accumulation. The genes shown with

H3K4me2 accumulation and potential transcriptional accessibility are C1qbp, C1d, Cfdp1, C8a,

C1q13, C1qtnf4, C1q12 and C1ql1.

42


developmental stages for complements. The tree-view shows the expression of C1qtnf genes

on E17.5, PN1, PN7 and PN15. These genes were divided into two clusters (C1-C2) according

to their H3K4me2 accumulation and/or H3K27me3 accumulation. The level of accumulation is

indicated by the brightness of red of the corresponding block. Black represents absence of

accumulation.

43

4.1.3.3. Epigenetic mapping of complement

As one of the important mediators in the inflammatory response, complements are closely

associated with inflammatory diseases. The C1qtnf family is a family of adipokine-related genes

(Zheng et al., 2011). Recent studies have suggested that two family members, C1qtnf4 and

C1qtnf9 are associated with cell apoptosis in disease (Li et al., 2011; Zheng et al., 2011). For our

study, we are interested in the association of complement genes with retinal diseases. Therefore,

we have selected the C1qtnf family as a representation of complement for epigenetic mapping.

Figure 5. Epigenetic mapping of C1qtnf family. Upper panel is the map of H3K4me2 and

H3K27me3 occupancy in C1qtnf genes at E17.5, PN1, PN7, PN15 and RD (PN28). The spikes

represent the level of accumulation of the gene. Transcription start sites are labeled in red and

alternative start sites are labeled in blue. The lower panel is a condensed view of H3K4me2

44

accumulation in other organs, such as bone marrow, cerebellum, cortex, heart, kidney, liver, lung

and spleen. The black bands represent occupancy of H3K4me2 accumulation.

Not all of the genes in this family have H3K4me2 accumulation at their transcription start site,

which means only C1qtnf3, C1qtnf4 and C1qtnf6 are transcriptionally accessible in the retina, as

well as other organs (Figure 5). C1qtnf3 and C1qtnf4 exhibit the most prominent H3K4me2

accumulation in retina compared to other family members. C1qtnf4, C1qtnf6 and C1qtnf9 have

an alternative transcription start site (ATSS). The H3K4me2 accumulation of C1qtnf4 was most

abundant at PN15, and this accumulation is distinct in the retina. H3K4me2 accumulation of

C1qtnf6 is shown in both TSS and ATSS in the retina and other organs. C1qtnf9 only exhibited

H3K4me2 accumulation at ATSS but not TSS in the retina, which is distinct compared to the

other C1qtnf members.

4.1.3.4. Epigenetic mapping of Toll-like receptors

Using the same methods above, we also performed epigenetic mapping for the Toll-like

receptor family, which is composed of important receptors that are stimulated by extrinsic factors

such as endotoxins and immune responses.

45

Figure 6. Epigenetic mapping of toll-like receptor family. Upper panel is the map of

H3K4me2 and H3K27me3 occupancy in toll-like receptor genes at E17.5, PN1, PN7, PN15 and

RD (PN28). The spikes represent the level of accumulation of the gene. Transcription start sites

are labeled in red and alternative start sites are labeled in blue. The lower panel is a condensed

view of H3K4me2 accumulation in other organs, such as bone marrow, cerebellum, cortex, heart,

kidney, liver, lung and spleen. The black bands represent occupancy of H3K4me2 accumulation.

According to the level of H3K4me2 accumulation, TLR2, TLR3 and TLR9 are

transcriptionally accessible during retina development, while the other nine TLRs, TLR1, TLR4,

TLR5, TLR6, TLR7, TLR8, TLR11, TLR12, and TLR13 lack H3K4me2 modified TSS during

retinal development (Figure 6). The pattern of H3K4me2 accumulation of the TLR genes, with

the exception of TLR1, TLR5, and TLR12, in the retina is mostly consistent with that of other

organs.

46

4.2. Epigenetic analysis of intracellular signaling genes of inflammatory/immune

response during retina development

4.2.1. Introduction

Intracellular signaling is an important process to transmit extracellular signals into the

nucleus and initiate transcription. PI3K-Akt, JAK-STAT, and NF-κB pathways are important

signaling pathways responsible for immune response signaling and activation. Here, we

specifically focus on the accessibility of transcription initiation sites of genes in these pathways.


In this study, we focused on members of the PI3K-AKT, JAK-STAT, and NF-κB families. Data

on these genes were collected from the database (GEO# GSE38500) we published previously

(Popova et al., 2012) and ENCODE/LICR Histone Mods by ChIP-Seq analysis.

4.2.3. Epigenetic analysis

4.2.3.1. Cluster analysis of PI3K-AKT signaling genes

The PI3K-AKT signaling genes from RefSeq database were grouped by hierarchical cluster

analysis based on the occupancy of H3K4me2 and H3K27me3 around the TSS during

development as described previously. Proportionally, half of the PI3K-AKT signaling pathway

genes are occupied by more H3K4me2 than H3K27me3 accumulation and the other half are

occupied by more H3K4me2 than H3K27me3 accumulation. Interestingly, Pik3cd3, Pik3cd4,

Pik3cd5, Pik3ap1, Pik3r5, Pik3cd.6, Pik3cb and Pik3c2b exhibit both H3K4me2 and H3K27me3

occupancy.

47


developmental stages for PI3K signaling molecules. The tree-view shows the expression of

PI3K-AKT signaling molecule genes on E17.5, PN1, PN7 and PN15. These genes were divided

into two clusters (C1-C2) according to their H3K4me2 accumulation and/or H3K27me3

accumulation. The level of accumulation depends on the redness of the correlated block. Black

represents absence of accumulation.

4.2.3.2. Cluster analysis of STAT signaling

We selected and analyzed several STAT signaling pathway genes by hierarchical cluster

analysis as described previously. Proportionally, half of the JAK-STAT signaling pathway genes

48

are occupied by more H3K4me2 than H3K27me3 accumulation and the other half are occupied

by more H3K4me2 than H3K27me3 accumulation. The JAK2 isoforms are more occupied by

H3K4me2 accumulation than H3K27me3 accumulation, which suggests this gene is more likely

to be transcriptionally accessed. STAT5 and JAK3 are more occupied by H3K27me3

accumulation than H3K4me2 accumulation, which indicates that these genes are less likely to be

transcribed during retina maturation (Figure 8).


developmental stages for JAK-STAT molecules. The tree-view shows the expression of

JAK-STAT genes on E17.5, PN1, PN7 and PN15. These genes were divided into two clusters

(C1-C2) according to their H3K4me2 accumulation and/or H3K27me3 accumulation. The level of

accumulation depends on the redness of the correlated block. Black represents absence of

accumulation.

49

4.2.3.3. Cluster analysis of NF-κB signaling pathway genes

We have also selected and analyzed several NF-κB signaling pathway genes with

hierarchical cluster analysis. Most genes in cluster 1 have higher H3K4me2 accumulation, and

most genes in cluster 2 have higher H3K27me3 accumulation (Figure 9). Proportionally, half of

the NF-κB signaling pathway genes are more occupied by H3K4me2 accumulation than

H3K27me3 accumulation, and the other half are more occupied by H3K27me3 accumulation

than H3K4me2 accumulation.

50


developmental stages for NF-κB signaling molecules. The tree-view shows the expression of

NF-κB signaling molecule genes on E17.5, PN1, PN7 and PN15. These genes were divided into

two clusters (C1-C2) according to their H3K4me2 accumulation and/or H3K27me3 accumulation.

The level of accumulation depends on the redness of the correlated block. Black represents

absence of accumulation.

4.3. Examination of NF-κB negative feedback signaling genes in the retina

4.3.1. Introduction

NF-κB is the major transcriptional factor that mediates many signaling cascades related to

immune responses. The NF-κB signaling pathway is very complicated and involves mediation

from both positive and negative regulators. Dysfunction of NF-κB regulators may result in

autoimmune diseases such as IBD, RA, and SLE. Here we focus on the transcription initiation

site accessibility and expression of NF-κB regulators.


In this study, we focused on the positive and negative regulators of the NF-κB family. Data

on these genes were collected from the database (GEO# GSE38500) we published previously

(Popova et al., 2012) and ENCODE/LICR Histone Mods by ChIP-Seq analysis.

4.3.3. Epigenetic mapping of NF-κB signaling pathway genes and its negative

feedback genes

4.3.3.1 Epigenetic mapping of NF-κB signaling genes

51

All of the upstream and downstream regulator genes in this family exhibit H3K4me2

accumulation at TSS, which suggests that the NF-κB regulators have high transcription

accessibility, and further implicates the essential roles of NF-κB regulation during retinal

development (Figure 10, 11). The H3K4me2 accumulation in the retina is mostly consistent with

the occupancy in other organs.

52

Figure 10. Epigenetic mapping of essential NF-κB pathway regulators part 1. Upper panel

is the map of H3K4me2 and H3K27me3 occupancy in essential NF-κB pathway regulator genes

53

at E17.5, PN1, PN7, PN15 and RD (PN28). The spikes represent the level of accumulation of the

gene. Transcription start sites are labeled in red and alternative start sites are labeled in blue.

The lower panel is a condensed view of H3K4me2 accumulation in other organs, such as bone

marrow, cerebellum, cortex, heart, kidney, liver, lung and spleen. The black bands represent

occupancy of H3K4me2 accumulation.

Figure 11. Epigenetic mapping of essential NF-κB pathway regulators part 2. Upper panel

is the map of H3K4me2 and H3K27me3 occupancy in essential NF-κB pathway regulator genes

at E17.5, PN1, PN7, PN15 and RD (PN28). The spikes represent the level of accumulation of the

gene. Transcription start sites are labeled in red and alternative start sites are labeled in blue.

The lower panel is a condensed view of H3K4me2 accumulation in other organs, such as bone

marrow, cerebellum, cortex, heart, kidney, liver, lung and spleen. The black bands represent

54

occupancy of H3K4me2 accumulation.

4.3.3.2. Epigenetic mapping of NF-κB negative feedback regulator genes

Tnfaip3/A20, Cyld, Cezanne, Usp21, Trafd1 and Pcbp-2 have been identified as negative

regulators of the NF-κB pathway. All of the negative regulators exhibit H3K4me2 accumulation at

TSS, as well as occupancy at ATSS except Cyld and Usp21. Evidence of the existence of these

ATSSs is consistent with the study by Popova and colleagues (Popova et al., 2012). These

genes also exhibit H3K4me2 accumulation in other organs at the TSS, but not at ATSS.

Figure 12. Epigenetic mapping of NF-κB negative feedback genes. Upper panel is the map

of H3K4me2 and H3K27me3 occupancy in NF-κB negative feedback genes at E17.5, PN1, PN7,

55

PN15 and RD (PN28). The spikes represent the level of accumulation of the gene. Transcription

start sites are labeled in red and alternative start sites are labeled in blue. The lower panel is a

condensed view of H3K4me2 accumulation in other organs, such as bone marrow, cerebellum,

cortex, heart, kidney, liver, lung, and spleen. The black bands represent occupancy of H3K4me2

accumulation.

4.3.4. Gene expression of NF-κB negative feedback genes in retina

4.3.4.1. Tnfaip3/A20 expression during retina development

We further compared and analyzed previous microarray results of the negative regulator

Tnfaip3/A20 with other retina specific genes, Rs1h, Abca4 and Rho from a retina microarray

database published from our lab (Zhang et al., 2006). The upper panel of Figure 16 represents

the comparison of gene expression between Tnfaip3/A20, Rs1h, Abca4 and Rho during retina

development. Expression of all 4 genes exhibits an increase around PN07 and reached its

maximum level at PN21 under normal conditions. The lower panel revealed a higher expression

of Tnfaip3/A20 compared to Tnfaip1 and Tnfaip2 when not stimulated. In this case, it is likely that

Tnfaip3/A20 may play an important role in retinogenesis.

56

Figure 13. Tnfaip3/A20 expression during developmental stages. The upper panel shows

the expression of Tnfaip3 (in blue), Rho, Abca4 and Rs1h from E12.5 to PN21. The lower panel

shows comparison of Tnfaip3, Tnfaip2 and Tnfaip1 expression from E12.5 to PN21.

4.3.4.2. Tissue specific Tnfaip3/A20 responses to LPS

In order to elucidate the role of Tnfaip3/A20 during retinal development, we confirmed the

RNA expression of Tnfaip3/A20 by RT-PCR analysis.

57

Figure 14. Tnfaip3/A20 primers. Tnfaip3-p1 and Tnfaip3-p2 are Tnfaip3 isoforms. Yellow

arrows represent primer set 1 which amplifies common sequence of both isoforms. Primer set 2

is depicted by blue arrows, which amplifies a unique sequence in Tnfaip3-p2.

Figure 15. PCR results for Tnfaip3/A20 in retina and spleen with/without LPS treatment.

Three B6WT mice were injected with 1X PBS (200ul) as control group. RNA from retina and

Tnfaip3-p1

Tnfaip3-p2

58

spleen were extracted and the expression of Tnfaip3P1, Tnfaip3P2 and beta-actin were

analyzed. Nine other mice were injected with 50ug/kg LPS (200ul) for either 1h, 24h or 72h.

Levels of Tnfaip3-p1, Tnfaip3-p2 and beta-actin were also analyzed via RT-PCR.

Two sets of primers for Tnfaip3/A20 were designed (Figure 14). Primer set 1 (Tnfaip3P1)

detects the common sequence of Tnfaip3-p1 and Tnfaip3-p2, while primer set 2 (Tnfaip3P2) is

specific to Tnfaip3-p2, which allows us to distinguish Tnfaip3-p2 from Tnfaip3-p1. With these

primers, we can determine the relative fraction of transcript isoform that is responsible for

Tnfaip3/A20 expression. We compared the expression of Tnfaip3/A20 in retina and spleen with

the designed primer sets (Figure 15). Under normal conditions, Tnfaip3/A20 is expressed in the

retina but not the spleen. When stimulated with LPS, both retina and spleen expressed

Tnfaip3/A20. By 24h after LPS injection, the expression of Tnfaip3/A20 in both retina and spleen

decreased. By 72h after LPS treatment, expression of Tnfaip3/A20 was almost completely

diminished in spleen, while its expression in the retina returned to its normal level. These results

provided evidence that Tnfaip3/A20 is locally expressed in the retina under both normal and

stimulated conditions, while expression of Tnfaip3/A20 in the spleen must be stimulated by LPS.

59

Figure 16. Statistical and comparative analysis for Tnfaip3 isoforms in retina and spleen.

Solid circle represents Tnfaip3P1 (P1), and solid square represents Tnfaip3P2 (P2). The p-value

is calculated via comparing the density of P1 and P2 by unpaired student t-test at different time

points after LPS injection (n=12).

Quantitative analysis confirmed our observation from the PCR result (Figure 15). Expression

level detected by both primer sets are the same (P>0.05) at 0h, 1h, and 24h after LPS injection

60

(Figure 16). However, expression of the two isoforms at 72h after LPS injection are statistically

different (P<0.01). In spleen, expression of the two isoforms is significantly different at the first

hour after LPS injection (P<0.01) while their expression at all other time points remain the same

(P>0.05).

4.3.4.3. Differential response of other NF-κB negative feedback regulator genes

To further test our hypothesis, we performed RT-PCR analysis to confirm expression of two

other NF-κB negative regulators, Pcbp2 and Trafd1. Pcbp2 has two isoforms, Pcbp2 isoform 1

and Pcbp2 isoform 2. Primer set 1 of Pcbp2 (Pcbp2-NT) detects the common sequence of Pcbp2

isoform 1 and 2, while primer set 2 (Pcbp2-AS) detects the specific sequence of Pcbp2 isoform 2

only. Expression of both Pcbp2 isoforms and Trafd1 exhibit the same pattern as Tnfaip3/A20,

which is expressed in the retina under normal conditions. After LPS stimulation, both of the

Pcbp2 genes and Trafd1 are expressed in the retina and spleen. In contrast to Tnfaip3/A20

expression, expression of Pcbp2 and Trafd1 did not decrease after 24h of LPS treatment in both

retina and spleen. The expression detected by Pcbp2-AS and Trafd1 are even more prominent

after 24h of treatment in the spleen, and did not disappear completely by 72h of LPS stimulation,

which is inconsistent with the pattern in the retina and expression pattern of Tnfaip3/A20.

61

Figure 17. PCR results for Pcbp2 and Trafd1 expression in retina and spleen

with/without LPS treatment. Three B6WT mice were injected with 1X PBS (200ul) as control

group. RNA from retina and spleen were extracted and the expression of Pcbp2-NT, Pcbp2-AS,

Trafd1 and beta-actin were analyzed.

62

Figure 18. Statistical analysis for Pcbp2-NT, Pcbp2-AS and Trafd1 expression comparison.

The expression of Pcbp2 isoforms and Trafd1 were compared in response to LPS treatment in

both the retina and spleen. Light grey represent gene expression at normal circumstance. Mild

63

grey represents gene expression after 24h of LPS treatment, and dark grey represents 72h after

LPS treatment.

Comparison of the expression of each gene between LPS untreated and treated conditions

showed that Pcbp2 isoform 2 (Pcbp2-AS) is the only gene which exhibited significant difference

in response to LPS treatment (P<0.01) in the retina while the other two genes showed no

statistical difference (P>0.05) (Figure 16). In the spleen, the expression of Pcbp2 isoforms

(Pcbp2-NT) and Trafd1 exhibited statistical significant difference in response to LPS treatment

(P<0.01).

64

CHAPTER 5

DISSCUSSION AND CONCLUSION

65

5.1. Interleukin receptors compared to interleukin themselves have more transcriptional

accessibilities in the retina

We have showed that among all the interleukin and interleukin receptor genes that have

H3K4me2 accumulation, 70% are interleukin receptors and 30% are interleukins, which

suggests that interleukin receptor genes are more transcriptionally accessible compared to

interleukins genes. The interleukin receptor genes which exhibited H3K4me2 accumulation are

Ifnar1, Ifnar2, Il11ra, 1l1rap, Il3ra, Il17rd, 1l10rb and Il4ra. Ifnar has distinct neuroprotective

functions in autoimmune diseases in the central nervous system. Its deletion in myeloid cells

aggravates diseases such as experimental autoimmune encephalomyelitis (EAE) and increases

lethality (Prinz et al., 2008). Ifnar1 exhibited the same function as Ifnar2, which is crucial for viral

and bacterial infection responses (Weerd et al., 2007). Il11ra is a receptor from the hematopoietic

cytokine receptor family. It assembles CNTF from a structural aspect, since both of them have a

immunoglobulin-like domain and a cytokine receptor-like domain (Dams-Kozlowska et al., 2012).

Il1rap (Il1 receptor accessory protein) is essential for Il1 receptor signaling, and participate in its

downstream regulation (Wesche et al., 1997). Il3ra has a beta subunit that is essential for

GM-CSF and Il5 high affinity binding and Il3 activation for immune responses (Woodcock et al.,

1994; Stomski et al., 1996). Il17rd mediates Il17 signaling and is important in neutrophil

recruitment. Deletion of Il17rd increases NF-κB activation via interaction with TRAF6 and

enhances Il6 expression (Rong et al., 2009; Mellet et al., 2012). Il17rd was detected in the retina

of zebrafish. It is positively controlled by FGF pathway, which establishes the nasal identity of

66

developing retina (Erickson et al., 2010). Il10rb is a receptor for Il10 induced signaling

transduction. Together with Ifnar1 and two other interferon receptors, they form a class II

cytokine receptor gene cluster on chromosome 21 (Kotenko et al., 2003). Il4ra plays an essential

role in IgE regulation via inducing differentiation of Th2 cells in allergy response such as asthma.

It has been suggested that the polymorphisms of Il4ra contribute to atopic phenotype

(Isidoro-Garcia et al., 2005). Il4ra has been found in the neural retina (glial cells) and non neural

retina region (RPE, choroid and sclera cells). It was detected from E20 retina, until P0 reached to

all layers, and most intensively expressed in the IPL. Around P14, the photoreceptor outer

segment had the most expression of Il4ra. It was also presented in OPL and IPL, which is

consistent with the pattern of Müller cell processes. In adult retina, Il4ra was only presented in

the photoreceptor outer segment. The same study also pointed out that Il4 suppresses the

proliferation of retinal progenitor cells via cAMP-PKA and promotes rod cell differentiation (da

Silva et al., 2008). Therefore, expression of Il4ra in the development of retina is crucial for rod

development, which explains the importance of Il4ra to be transcriptionally accessible in the

retina.

The interleukin related genes, which exhibited H3K4me2 accumulation are Il17d, Il6st, Il7,

Il15 and Il1f5. Il17d is a novel member of the Il17 family (Starnes et al., 2002). LPS-induced

inflammatory response enhances production of Il6 (NF-κB dependent), TNFα, MIP1α, and

MIP1-βvia TLR4 in human monocytes (Guzzo et al., 2012). Il6st functions as part of the cytokine

receptor complex, and is shared by Il6, CNTF, LIF and OSM (Sarkoze et al., 2012; Necula et al.,

67

2012). Il7 is a hematopoietic growth factor that is important for T cell and B cell development. It

can be produced by intestinal epithelial cells, and plays its essential roles in lymphoid cell

survival (Cai et al., 2012; Liang et al., 2012; Venet et al., 2012). In the retina, Il7 is suggested to

reflect IOP elevation in rodent (Naskar and Thanos, 2006). It is also the primary stimulator of

RPE MCP1 and Il8, which could be important in diseased retina tissue when proinflammatory

cytokines are low (Elner et al., 1996). In this case, it may be crucial for Il7 to be transcriptional

accessible in the retina, which was shown in our study. Il1f5 belongs to interleukin 1 family. It

inhibits Il1 and Il6 induced NF-κB activation (Johnston et al., 2011; Vigne et al., 2011).

Most of the genes listed above is not well studied, even less so their roles in the retina.

Expression of a few of these genes, however, have been associated with retinal development

and implicated in the rescue of immune response in diseased retina.

5.2. A number of complements are transcriptionally accessible at the alternative

transcription start site in the retina

Our previous study has shown that alternative transcripts of complements are expressed in

the retina. For example, of the 9 genes in the C1qtnf family, C1qtnf4, C1qtnf6 and C1qtnf9 exhibit

an alternative start site. Overexpression of C1qtnf4, also known as CTRP4 induce NF-κB and

Il6/STAT3 signaling like a classical cytokine pathway. It is also suggested as a regulator of

inflammatory processes including cell apoptosis in cancer cells, and may be a new drug target

for cancer therapy (Li et al., 2011). C1qtnf6 is generally expressed in fat tissue (Wong et al.,

68

2008). It stimulates phosphorylation of MAPK, and induces Il10 expression (Kim et al., 2011).

C1qtnf6 is also suggested to activate the PI3K-AKT pathway and contribute to tumor

angiogenesis found in hepatocellular carcinomas (Takeuchi et al., 2011). In the retina, C1qtnf6

modulates photoreceptor death in light induced photoreceptor degeneration (Rutar et al., 2011).

It is slightly induced after 24h of bright light stimulation, and declines post exposure (Rutar et al.,

2011). C1qtnf9 is highly enriched in adipose tissue. It may activate AMPK, AKT, and MAPK and

stimulate glucose uptake. It also mediates vasorelaxation in an epithelium-dependent manner

(Zheng et al., 2011).

Although the role of C1qtnf4, C1qtnf6, and C1qtnf9 and their association with the retina have

not been investigated, it is possible that these three members of the C1qtnf family could

associate with cell apoptosis in the retina, and contribute to progressive retinal degeneration.

5.3. The toll-like receptor family has limited transcriptional accessibility in the retina.

The Toll-like receptor family is the major family that recognizes and distinguishes between

self and non-self pathogens (Medzhitov and Janeway, 2002). The thirteen family members are

localized in different cell compartments - TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed on

the plasma membrane while TLR3, TLR7, TLR8, and TLR9 are expressed in the

endo(lyso)somes (Barton and Kagan, 2009). In our study, only TLR2, TLR3, and TLR9 are

transcriptionally accessible at TSS during retinal development. TLR3 is a type I intracellular

transmembrane protein which recognizes viral double stranded RNA, mimicked by

polyriboinosine-polyribocytidylic acid (poly I:C). Upon stimulation, TLR3 triggers the activation of

69

NF-κB signaling via the MyD88-independent pathway, and activates the expression of cytokines,

chemokines and IFNa/b genes (Alexopoulou et al., 2001; Menager et al., 2009). High levels of

TLR3 are also found in the central nervous system (Alexopoulou et al., 2001). It is suggested that

TLR3 is involved in innate immune response and neuronal injury/ viral infection (Lafon et al.,

2006; Menager et al., 2009). Study by Kumar and colleagues in 2004 demonstrated expression

of TLR1-7, 9, and 10 in RPE cells, and that TLR3 is one of the most highly expressed TLRs

(Kumar et al., 2004). In our study, epigenetic mapping of the Toll-like receptor family genes

showed H3K4me2 accumulation in TLR3 gene in the retina, which indicate TLR3 can be

transcriptionally accessed in the retina. This is consistent with the previous study of TLR3 in the

central nervous system. However, the role of TLR3 in RPE cells is not well understood. While it is

suggested that TLR3 protects the RPE cells from oxidative stress induced disease such as AMD

through STAT3 (Patel et al., 2012), TLR3 has also been suggested to be responsible for the

cause of retinopathy (Shiose et al., 2011).

Compared to TLR2, which is localized on the cell surface, endogenous TLR9 is localized

intracellularlly in normal macrophage. TLR9 recognizes unmethylated CpG motifs in bacterial

DNA endosome (McGettrick and O’Neil, 2010). Activated by dendritic cell induced Il12, the CpG

motifs are methylated on cytosine residues, and elicits Th1-like immune responses (Takeda et al.,

2003). The TLR9 induced signaling cascade is slower compared to LPS-induced activation

(Hemmi et al., 2000). TLR9 expression has been detected in RPE and Müller cells in the retina

(Ebihara et al., 2007; Kumar et al., 2012). In our study, expression of TLR9 peaks at PN7, and

disappears at PN15. This seems consistent with the development of RPE cells, which initiates at

70

PN6 and peak at PN9 (Hooks et al., 1989). It is also consistent with the differentiation of Müller

cells, which initiates at PN11 and decline at PN16 (Bhattacharjee and Sanyal, 1975).

TLR2 can recognize peptidoglycan and lipoprotein in various microorganisms, including

Gram-positive bacteria, Gram-negative bacteria, mycobacteria, etc (Takeda et al., 2003) by

cooperating with TLR1 and TLR6 during microbial recognition (Takeuchi et al., 1999; Ozinsky et

al., 2000; Hirschfed et al., 2001; Werts et al., 2001). It also recognizes atypical LPS from

Leptospira interrogans and Porphyromonas gingivalis, which are structurally and functionally

different from enterobacteria LPS recognized by TLR4 (103,104). Expression of TLR2 is

restricted to antigen presenting cells and endothelial cells, while TLR1 and TLR6 are expressed

in various cell types (Muzio et al., 2000). Study from Fujimoto and colleagues have pointed out

that CNV, common in AMD is caused via TLR2 in RPE cells (Fujimoto et al., 2010). Pretreatment

of TLR2 ligand attenuates retinal inflammatory responses but enhances phagocytic activity

(Kochan et al., 2012). However, the expression of TLR2 in our study suggests that TLR2 is

transcriptionally accessible in the retina, which means that TLR2 could be locally expressed, and

may play an important role in retinal immune response.

5.4. Most of the genes in NF-κB signaling are transcriptionally accessible in the retina

NF-κB is an important transcriptional factor for many responses. In our study, we have

shown that NF-κB signaling molecules are largely involved in retina development, where

one-third of the NF-κB signaling molecules selected exhibit H3K4me2 accumulation. The

transcription start site of essential NF-κB regulators were all identified in the retina, as well as in

71

other organs. Also, among the NF-κB negative feedback regulators, A20, Cezanne, Pcbp2, and

Trafd1 were presented with alternative start sites specifically in the retina. These results provided

evidence that NF-κB signaling molecules can be activated locally in the retina, and that the

NF-κB pathway regulation is crucial to retina development in mice. Moreover, the negative

feedback regulators with alternative start site suggest these alternative transcripts may be retina

specific.

Not only can the NF-κB pathway be stimulated by inflammatory responses, but also be

activated via light stress. Wu and colleagues have identified increased NF-κB DNA binding

activity and IκBα mRNA expression in mice photoreceptor cells after exposure to intense green

light (Wu et al., 2002), which supports previous observation that NF-κB is crucial in anti-apoptotic

process (Kaltschmidt et al., 1999; Krishnamoorthy et al., 1999; Crowford et al., 2001; Mattson et

al., 2001).

Recent studies in Drosophila have established that NF-κB signaling molecules regulate

expression of genes related to immune response peptides and proteins (Hetru and Hoffman,

2009) via toll and Imd pathways in its host defense (De Gregorio et al., 2001; Irving et al., 2001).

NF-κB also functions as an important regulator in Drosophila embryonic development and

differentiation through the toll pathway (Baldwin, 1996).

5.5. Constitutive expression of the genes related to NF-κB negative feedback in mature

retina

72

Tnfaip3/A20 mediates negative feedback of the NF-κB pathway by targeting the upstream

signaling molecules. In our study, we found that Tnfaip3/A20 is locally expressed in the retina

with or without LPS stimulation, whereas in the spleen, Tnfaip3/A20 expression must be induced

by LPS. In the retina, expression of Tnfaip3/A20 decreases until 24h after LPS injection but by

72h, expression level of Tnfaip3-p1 returns to normal while expression of Tnfaip3-p2 continues

to decline. Contrary to the retinal expression of Tnfaip3/A20, expression of Tnfaip3/A2-p1 in the

spleen is initiated upon administration of LPS but begins to decrease by 24h and is absent by

72h. In contrast, LPS injection has no effect on Tnfaip3/A20 expression in the spleen. Besides

Tnfaip3/A20, Pcbp2 and Trafd1 are two other negative feedback regulators of the NF-κB

pathway that have been characterized in the literature. Pcbp2 negatively regulates MAVS

mediated signaling via degradation, which is crucial to preventing excessive inflammatory

response (You et al., 2009). Trafd1 has been suggested to suppress TLR4 mediated NF-κB

activation by targeting TRAF6 and TRAF3 (Mshima et al., 2005). Deficiency of Trafd1 results in

over-response of the immune system to LPS stimulation and poly ( I:C) induction (Sanada et al.,

2008). In our study, expression of both isoforms of Pcbp2-NT and Trafd1 follows the same

pattern of expression as Tnfaip3/A20, which is constitutively expressed in the retina. The

alternative transcript of Pcbp2 in the retina exhibits the same pattern of expression as the

canonical transcript of Pcbp2 and Trafd1 in the spleen; their expression increased dramatically

only after LPS induction. Interestingly, unlike Tnfaip3/A20, the expression of Pcbp2 isoforms and

Trafd1 was consistent in response to LPS treatment, which suggest that the proteasomal

degradation of these genes are different. The expression of Pcbp2 isoform 2 and Trafd1 is

73

prominent 24h after LPS treatment in the spleen compared to non-treated group, and it was

reduced after 72h of treatment. This may also support the idea that these genes participate in

more than one signaling pathway, and that they may regulate different pathways in different

organs.

5.6. Conclusion

During development, many immune response genes in the retina are transcriptionally

accessible. The majority of these genes are interleukin receptors and intracellular signaling

genes in the PI3K-AKT, JAK-STAT, and NF-kB pathways. Most importantly, a large number of

NF-κB signaling genes are occupied by H3K4me2 at TSS, suggesting that of these pathways,

the NF-kB is the most critical for retina maturation. Negative feedback regulators of the NF-κB

signaling pathway also exhibit high transcriptional accessibility during retina maturation.

Tnfaip3/A20, Pcbp2 and Trafd1, in particular, exhibit unique expression patterns in the retina

compared to the spleen, suggesting that these three negative regulators may be crucial in the

maintenance of retinal homeostasis, and that the retina is an immune privilege site.

74

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