Core Promoter Recognition Complex Switching in Liver Development and Regeneration by Joseph Anthony D’Alessio A.B. (Bowdoin College) 1998 A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Molecular and Cell Biology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Robert Tjian, Chair Professor Michael Levine Professor Iswar Hariharan Professor David V. Schaffer Fall 2009
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Core Promoter Recognition Complex Switching in Liver Development and Regeneration
by
Joseph Anthony D’Alessio A.B. (Bowdoin College) 1998
A dissertation submitted in partial satisfaction
of the requirements for the degree of
Doctor of Philosophy
in
Molecular and Cell Biology
in the
Graduate Division
of the
University of California, Berkeley
Committee in charge:
Professor Robert Tjian, Chair Professor Michael Levine Professor Iswar Hariharan
Professor David V. Schaffer
Fall 2009
Abstract
Core Promoter Recognition Complex Switching
in Liver Development and Regeneration
by
Joseph Anthony D’Alessio
Doctor of Philosophy in Molecular and Cell Biology
University of California, Berkeley
Professor Robert Tjian, Chair
The exquisite structural and functional complexity of the mammalian body
requires the exactingly precise spatial and temporal regulation of gene expression. The
most critically regulated step of which is the transcription of DNA to RNA by the
elaborate interplay of sequence-specific activators and repressors, chromatin modifiers,
coactivators, the basal machinery and RNA polymerase II. Until recently, developmental
stage and tissue-specific gene expression patterns were believed to be regulated primarily
by the combinatorial actions of DNA binding activators and repressors, while the core
machinery was held to be invariant. New evidence suggests that significant differences
in coactivator and core promoter recognition complex composition between cell types
and developmental time points may facilitate the global changes in gene expression
programs necessary to confer functional diversity. Because of its critical role in
vertebrate development and homeostasis, the role of coactivator and core promoter
recognition complex switching in the developing liver was examined.
This work shows that mouse liver progenitors or hepatoblasts contain significant
levels of the canonical core promoter recognition complex TFIID, including the TATA
binding protein and multiple associated factors or TAFs, and the canonical coactivator
complex Mediator. These complexes and their constitutive proteins are significantly
downregulated in adult hepatocytes. Furthermore, the promoters of several TFIID
components become enriched for repressive chromatin marks in adult hepatocytes, and an
in vitro model of liver development recapitulates the downregulation of these complexes
observed in vivo. In contrast, expression of the TBP-related factor TRF3, the TAF7
paralogue TAF7l, and TAF13 is maintained or induced upon hepatic differentiation.
Additionally, these proteins associate with high molecular weight complexes in vitro
where they are enriched at hepatocyte-specific promoters, and their depletion attenuates
hepatic gene induction. Together these observations support a model wherein liver
development and the induction of hepatic gene expression requires the down regulation
of TFIID and its replacement with one or more complexes likely containing TRF3,
TAF7l and TAF13.
For my parents
Anne and Richard D’Alessio
who have supported all my adventures
and
with appreciation for Laurie McDonough
my best friend
Table of Contents
Chapter 1: Introduction
Summary 1
TFIID, TAFs, and the Basal Transcription Machinery 3
Alternative TAF Complexes, TBP-Related Factors, 7 and Tissue-Specific TAFs
TAFs in Metazoan Development and Differentiation 11
Embryonic and Postnatal Liver Development 14
Hepatic Regeneration 18
Embryonic Stem Cells and Therapeutic Approaches 22
Figures 26
References 32
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
Summary 54
Introduction 55
Results 58
Discussion 68
Materials and Methods 71
Figures 76
References 94
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Summary 99
Introduction 100
Results 110
Discussion 119
Materials and Methods 124
Figures 129
References 145
Chapter 1: Introduction 1
Chapter 1: Introduction
Summary
The precise spatial and temporal regulation of gene expression essential to
metazoan development and cellular homeostasis requires a complex interplay between
sequence-specific activators and repressors, coactivators, chromatin modifiers, general
transcription factors (GTFs), and RNA polymerase II (PolII). The first and most
regulated step in this process is the exacting recognition of unique gene-specific DNA
regulatory sequences by diverse activator proteins. These activators then recruit the core
promoter recognition complex TFIID consisting of the TATA box binding protein (TBP)
and 12-15 associated factors (TAFs) to the site of transcription. Subsequently,
coactivators including the Mediator complex (Med), chromatin modifiers, and the
additional GTFS TFIIA-F are recruited to the core promoter to form the preinitiation
complex (PIC). This allows for the recruitment of PolII and the start of productive RNA
transcription.
Historically, developmental stage and tissue-specific patterns of gene expression
were thought to be determined primarily by DNA regulatory sequences and their
associated activators, while the general transcription machinery including TFIID was
held to be invariant (reviewed by Thomas and Chiang 2006). However, recent studies
have shown that during skeletal muscle myogenesis a novel mechanism of regulating
global patterns of gene expression by switching of core promoter recognition complexes
is employed (reviewed by Reina and Hernandez 2007). Whether this novel mechanism
Chapter 1: Introduction 2
of transcriptional regulation exists in other tissues and developmental programs or is
restricted to muscle is currently unknown.
Chapter two examines patterns of TBP and TAF expression in diverse adult
mouse tissues and finds that they are significantly down regulated in the adult liver.
Further by purifying fetal liver progenitors (hepatoblasts), partially differentiated
neonatal hepatocytes, adult hepatocytes, and cycling regenerative hepatocytes, I
demonstrate that TFIID is significantly upregulated in liver progenitors and entirely
absent from the fully differentiated cell type, while at intermediate levels in slowly
dividing or not fully differentiated populations. In striking contrast, the TBP-related
factor TRF3 and TAF13 are expressed at the same levels throughout liver development
and the unique TAF paralogoue TAF7l is highly induced upon differentiation.
Importantly, these changes occur at both the transcriptional and protein levels and can be
reconstituted in an in vitro cellular model of liver differentiation.
The third chapter of this thesis confirms the presence of TRF3, TAF7l, and
TAF13 polypeptides in differentiated liver cells and provides evidence that they are
components of one or more high molecular weight complexes in vivo. Furthermore,
RNAi mediated depletion of each of these three proteins attenuates hepatic gene
induction in an in vitro model of liver differentiation, and all three proteins show varying
degrees of enrichment at the proximal promoters of hepatocyte-specific genes. Finally,
an embryonic stem cell based hepatic differentiation protocol suggests that these changes
in core promoter recognition complex architecture may extend beyond the murine model.
Chapter 1: Introduction 3
TFIID, TAFs, and the Basal Transcription Machinery
Proteins, the basic functional units of every living cell, are produced by the
transcription of DNA to messenger RNA, the splicing and nuclear export of this mRNA,
and the translation of mRNAs to polypeptides in a cell’s cytoplasm; a process known as
the Central Dogma (Crick 1958). The most critical and regulated step in this process is
the precise transcription of protein coding regions within a cell’s DNA by RNA
polymerase II (PolII) to form mRNA. The recruitment of PolII and initiation of
transcription at specific genes requires the exquisite coordination of hundreds of
polypeptides including the core promoter recognition complex TFIID (Figure 1) (Thomas
and Chiang 2006).
TFIID was initially identified as a biochemical activity required for in vitro
transcription by PolII (Matsui et al. 1980). Upon further purification, it was identified as
a 750kD complex containing the TATA box binding protein (TBP) and 12-15 associated
factors (TAFs) that are required for activated transcription both in vitro and in vivo
(Dynlacht et al. 1991; Pugh and Tjian 1991). It is now known that both TBP and most of
the TAFs are highly conserved in yeast (S. cerevisiae), worms (C. elegans), flies (D.
melanogaster) and humans (H. sapiens) and partially conserved in the metazoan
predecessor M. brevicollis, suggesting an ancient evolutionary origin (Burley and Roeder
1996; Albright and Tjian 2000; King et al. 2008).
The process of regulated transcription takes place by the stepwise assembly of the
preinitiation complex (PIC), followed by promoter escape, productive elongation, and
termination. PIC assembly is initiated through the precise recognition and binding of
Chapter 1: Introduction 4
distinct DNA sequences or enhancers within a gene’s distal or proximal regulatory
regions by a diverse set of tissue and developmental stage-specific transcriptional
activators. These activators in turn position TFIID at the core promoter through binding
of their activation domains either directly to TBP or a subset of specific TAFs (Stringer et
al. 1990; Chen et al. 1994; Thut et al. 1995). TFIID’s affinity for the core promoters is
further stabilized by its recognition of conserved motifs within the promoter itself
through both TBP and a limited number of TAFs (Smale and Kadonaga 2003). The most
widespread and important of these motifs include the TATA box (-30), the initiator (Inr,
+1), and the downstream promoter element (DPE, +30), while unique core promoter
elements continue to be discovered and their significance analyzed (Juven-Gershon et al.
2008). Currently, it is poorly understood whether distinct core promoter recognition
complexes are selectively recruited to specific genes based on their preference for certain
core promoter motifs (Muller et al. 2007).
TFIID’s association with promoter DNA is further stabilized through the
sequential recruitment of heterodimeric TFIIA, which can bind directly to TBP, TAFs
and activators, and the single subunit TFIIB, which interacts with TFIID, PolII and
promoter DNA itself (Maldonado et al. 1990). As part of this heterotrimeric complex,
TFIIB in turn recruits TFIIF, which maintains multiple contacts with, and thus brings to
the promoter, the PolII holoenzyme (Ha et al. 1993). Subsequently, TFIIF recruits
heterodimeric TFIIE, which stabilizes PolII binding and primarily functions to recruit the
large multisubunit TFIIH, which posses multiple enzymatic activities required for the
initiation of transcription (Maxon et al. 1994). Hence, TFIIH contains a helicase activity
Chapter 1: Introduction 5
necessary for the melting of promoter DNA, an ATPase activity necessary for formation
of the first phosphodiester bond, and a kinase domain which phosphorylates the C-
terminus of PolII to signal the transition from initiation to productive elongation (Lu et al.
1992; Holstege et al. 1996). Thus, once recruited to the core promoter by sequence-
specific activators, TFIID coordinates the stepwise assembly of all general transcription
factors required for initiation of productive PolII transcription.
Extensive structural and mapping studies have begun to provide a picture of how
TBP and the TAFs are assembled and positioned within the larger TFIID holoenzyme
(Cler et al. 2009). One of the first insights into TFIID structure came from the
identification of histone fold domains within several of the TAFs, leading to speculation
that TFIID may contain nucleosome like octomers. Biochemical studies have confirmed
that TAFs with like histone fold domains do pair to form heterodimers that make up the
basic structural subunits of the complex, including the pairs TAF4-TAF12, TAF6-TAF9,
TAF8-TAF10, and TAF11-TAF13 (Selleck et al. 2001; Leurent et al. 2002). Though the
exact stoichiometry of TAFs within the complex is unclear, biochemical studies suggest
that certain TAFs, including TAF1, TAF2, and TAF7, are present as a single copy while
the majority of TAFs are present as two or more subunits per TFIID molecule (Sanders et
al. 2002). Though X-ray crystallographic structures of intact TFIID have not yet been
solved, lower resolution electron microscopy and particle reconstruction has provided
some insight to the three dimensional structure of the complex (Andel et al. 1999; Brand
et al. 1999; Sanders et al. 2002). These structures reveal a tri-lobed horseshoe like
structure in which TBP can be localized to the central cleft, suggesting that this is the
Chapter 1: Introduction 6
sight of DNA binding. Further, TAF12, TAF4, TAF6, and TAF9 appear to be present in
each lobe, while TAF5 is present in the linker region joining all three lobes consistent
with a scaffolding function (Leurent et al. 2004). RNAi and overexpression studies in
insect cells suggest that TAF4, TAF5, TAF6, TAF9, and TAF12 are essential for the
formation of a stable core complex in vivo, which is then decorated by additional TAFs to
form holo-TFIID (Leurent et al. 2002; Wright et al. 2006).
Through a combination of in vitro and in vivo experiments, the specific functions
of individual TAFs have been greatly illuminated (Albright and Tjian 2000). A subset of
TAFs has been found to bind known sequence-specific activators and thus link these
proteins’ activation domains to the rest of the basal machinery. Some of these observed
interactions include binding of p53 to TAF6 and TAF9, binding of SP1 and Pygopus to
TAF4, binding of VP16 to TAF9, and binding of multiple activators to TAF7 (Goodrich
et al. 1993; Weinzierl et al. 1993a; Chiang and Roeder 1995; Thut et al. 1995; Wright and
Tjian 2009). Yet other TAFs bind specific motifs within the core promoter to help
stabilize TFIID position and PIC assembly. Hence, TAF1 and TAF2 can bind the Inr
element while TAF6 and TAF9 contact the DPE (Verrijzer et al. 1995; Burke and
Kadonaga 1997). More recently, some TAFs have been shown to interact directly with
chromatin marks such as TAF1 with acetylated histone tails and TAF3 with trimethylated
histone H3 lysine 4 residues (Jacobson et al. 2000; Vermeulen et al. 2007). Interestingly,
TAF1 possesses kinase, ubiquitin ligase, and acetylase enzymatic activities which may
act on histones or activators to further modulate transcription (Wassarman and Sauer
Chapter 1: Introduction 7
2001). Thus, individual TAFs serve specific functions within the context of the larger
complex, many of which are yet to be fully understood.
Alternative TAF Complexes, TBP-Related Factors, and Tissue-Specific TAFs
While TFIID is thought to be ubiquitously expressed and present at most genes,
several complexes have been discovered which contain a subset of TAFs, are free of
TBP, and likely act on a more limited number of promoters (Figure 2). The human TBP-
free TAF-containing complex (TFTC) which contains many of the TAFs as well as
additional proteins not found in TFIID, is able to bind multiple activators and facilitate in
vitro transcription, though its role in vivo is not well understood (Wieczorek et al. 1998).
The yeast Spt-Ada-GCN5 acetyltransferase complex (SAGA) contains both overlapping
and unique subunits with TFTC and appears to be important in the activation and
recruitment of free TBP to a subset of mostly stress responsive genes (Grant et al. 1998;
Huisinga and Pugh 2004). Similarly, SAGA-like (SLIK) and the human Spt3-TAF9-
GCN5L acetyltransferase complex (STAGA) have very similar composition to SAGA
and likely many of the same functions but are less well studied (Martinez et al. 1998;
Pray-Grant et al. 2002). The p300/CBP-associated factor (PCAF) complex has many
similarities to yeast SAGA and is involved in both global histone modifications and
locus-specific coactivation; additionally its disruption has been implicated in oncogenic
transformation (Ogryzko et al. 1998; Nagy and Tora 2007). Hence, while the
physiological roles of these alternative TAF containing complexes are not yet fully
Chapter 1: Introduction 8
understood, it is clear that TAFs have important functions outside the context of
canonical TFIID.
To date three distinct TBP-related factors (TRFs) or TBP-like proteins (TBPL)
have been discovered, from worms to humans, and their biological significance is
beginning to be unraveled (Figure 2) (Aoyagi and Wassarman 2000; Hochheimer and
Tjian 2003). TBP-related factor 1 (TRF1) was the first of these proteins to be identified
and appears to be unique to Drosophila, where it is highly expressed in the nervous
system and testes (Crowley et al. 1993). Similarly to TBP, TRF1 is found in a large
complex, binds TFIIA, TFIIB, and TATA containing DNA, and can promote PolII
transcription in vitro (Hansen et al. 1997). However, TRF1 appears to be distinct from
TBP in that its expression is restricted to a limited number of tissues, it is present at
relatively few promoters, and it also binds to a unique TC box core promoter element
(Holmes and Tjian 2000). Initially identified based on homology, TBP-related factor 2
(TRF2) is found from worms to humans and is more closely related to TBP than TRF1
(Dantonel et al. 1999; Rabenstein et al. 1999). Though it does interact with TFIIA and
TFIIB, TRF2 fails to bind a canonical TATA box and appears to bind novel promoters
not occupied by TBP or TRF1 (Hansen et al. 1997). Hence, it has been suggested that
TRF2 may also act as a repressor by disrupting PIC formation at TATA containing
promoters (Moore et al. 1999). Further, TRF2 is part of a high molecular weight
complex which lacks TAFs but contains known chromatin remodeling factors
(Hochheimer et al. 2002). Knockdown studies in worms and frogs (X. laevis) showed
that loss of TRF2 caused early embryonic arrest through the disruption of developmental
Chapter 1: Introduction 9
gene expression (Dantonel et al. 2000; Veenstra et al. 2000); however, TRF2 knockout
mice are viable with the only apparent phenotype being disrupted spermiogenesis (Zhang
et al. 2001).
The most recent and perhaps most interesting of these proteins to be identified is
TBP-related factor 3 (TRF3/TBPL2). Initially isolated based on the near identity of its
C-terminus to that of TBP including the DNA and GTF binding domains, TRF3 is
conserved in vertebrates from fish (Fugu) to humans but is absent in lower metazoans
(Persengiev et al. 2003). Initial reports showed that it was widely but variably expressed
in adult mouse and human tissues, migrated as part of a larger 150-200 kD complex, and
that its nuclear import was regulated during the cell cycle asynchronously from that of
TBP. Subsequent studies showed TRF3 to be highly enriched in the ovary and to a lesser
extent in the testes where it had a different pattern of nuclear import than TBP. However,
these reports conflicted as to whether TRF3 is expressed in early embryogenesis
following fertilization (Xiao et al. 2006; Yang et al. 2006; Gazdag et al. 2007; Jacobi et
al. 2007). Additionally, one of these studies found that TRF3 and TBP occupied unique
sets of promoters in mouse embryonic stem cells, while two others showed that TRF3 but
not TBP was required for the transcription of a majority of embryonic genes.
Knockdown studies in frogs and zebrafish (D. rerio) determined that TRF3 is required for
embryogenesis and may be able to partially rescue loss of TBP in the early embryo
(Bartfai et al. 2004; Jallow et al. 2004). Interestingly, regulation of the mespa gene by
TRF3 is shown to be the earliest and an essential step in the commitment of mesoderm to
hematopoietic precursors, suggesting that TRF3 plays a role in cell-type-specific
Chapter 1: Introduction 10
differentiation programs (Hart et al. 2007). Perhaps the best evidence for TRF3’s role in
tissue-specific differentiation comes from studies of the transition from muscle precursors
to mature muscle fibers. In this myogenic program it was found that canonical TFIID,
including both TBP and most of the TAFs, is completely degraded, while a unique
complex of TRF3 and TAF3 is retained in the adult cell type (Deato and Tjian 2007).
Furthermore, knockdown of TRF3 blocks myogenic differentiation and TRF3 but not
TBP is enriched at the promoters of key myogenic genes. Additional in vitro dissection
of this mechanism found that the TRF3/TAF3 complex cooperates with the myogenic
activator MyoD to initiate transcription of the myogenin promoter, and that this complex
is necessary and sufficient for the process (Deato et al. 2008).
In addition to TBP-related factors, a series of novel tissue-specific TAF paralogs
have been identified which further expand the diversity of core promoter recognition
complexes (Figure 2). Apparently unique to flies are the testes-specific TAFs, no hitter
(dTAF4b), cannonball (dTAF5b), ryan express (dTAF12b), and meiosis I arrest
(dTAF6b), all of which are required for spermatogenesis and normal germ cell-specific
gene expression (Hiller et al. 2001). Originally isolated from B-cells and highly
expressed in the testes and ovary, human TAF4b is the best understood tissue-specific
TAF. It associates with a slightly altered TFIID, which may or may not contain copies of
TAF4 and is required for expression of a subset of ovary-specific genes (Freiman et al.
2001; Geles et al. 2006). Furthermore, TAF4b knockout mice display defects in
folliculogenesis and spermatogenesis but no other apparent phenotypes, consistent with a
germ cell-specific pattern of expression and function (Falender et al. 2005). Similarly,
Chapter 1: Introduction 11
abundant expression of TAF7l coincides with reduced TAF7 expression in mouse
spermatids, and TAF7l associates with TBP and TAF1 presumably to form an altered
TFIID like complex (Pointud et al. 2003). Additionally, TAF7l knockout mice produce
abnormal sperm, have reduced fertility and overall weight, and show altered patterns of
testes-specific gene expression (Cheng et al. 2007). However, to date the full range of
phenotypes of these mice have not been characterized. The less well-studied TAF5l has
been associated with an increased risk of type I diabetes, but its pattern of expression and
association with TFIID remain to be determined (Cooper et al. 2007). Similarly, initial
characterization of TAF9l shows that it is a component of both TFIID and TBP-free
complexes, and that its loss affects the expression of a unique and overlapping set of
genes from that of TAF9 (Frontini et al. 2005). Finally, cell-type-specific alternative
splicing of TAF6 and possibly other TAFs may further expand the diversity of core
promoter recognition complexes (Weinzierl et al. 1993b).
TAFs in Metazoan Development and Differentiation
The central role TAFs and canonical TFIID in organismal development is
supported by the initial discovery of several TAFs in forward genetics screens and
confirmed by the requirement for many others as shown in depletion and knockout
experiments. Despite these findings, most TAFs, with the exception of tissue-specific
paralogs, are assumed to be ubiquitously expressed and canonical TFIID present at a
majority of promoters in nearly all tissue types. Hence, the first evidence of TFIID’s in
vivo function came from mutations in TAF4 and TAF6, which were homozygous
Chapter 1: Introduction 12
embryonic lethal and prevented proper complex formation in a sensitized Drosophila
suppressor screen (Karim et al. 1996; Sauer et al. 1996). Further analysis of the
heterozygous mutants showed a dosage dependent requirement for these TAFs as co-
activators of a known transcriptional activator at two important embryonic promoters
(Zhou et al. 1998; Pham et al. 1999). An independent mutation in TAF9 was found to
have dosage dependent affects on the expression of multiple genes, and these different
affects are potentially influenced by the genes differing core promoter architecture
(Soldatov et al. 1999). Finally, loss of function mutations in TAF1 were found to affect
the development of specific Drosophila tissues including the eye, ovaries, wing and
bristle by altering cell cycle progression and tissue-specific differentiation (Wassarman et
al. 2000).
Initial knockout studies in mice showed that loss of TAF8 or TAF10 destabilized
TFIID resulting in apoptosis of the blastocyst's inner cell mass and embryonic lethality,
though trophoblast viability appeared to be unaffected (Voss et al. 2000; Mohan et al.
2003). Conditional TAF knockout mice, which avoid the embryonic lethality phenotype,
are providing greater insight to tissue-specific TFIID function. As expected, a
conditional TAF4 allele failed to produce viable offspring when deleted in ES cells, but
was successfully employed to generate proliferative embryonic fibroblasts devoid of
TAF4 expression (Mengus et al. 2005). While these cell lines divided normally at routine
serum concentrations they displayed altered morphology, accelerated serum independent
growth, and disrupted expression of genes responsible for TGF signaling. Targeted
deletion of TAF4 in basal keratinocytes demonstrated that it is absolutely required for
Chapter 1: Introduction 13
fetal epidermis differentiation but partially dispensable for adult skin maintenance
(Fadloun et al. 2007). Furthermore, TAF4 inactivation increased the incidence of
epidermal hyperplasia, and this phenotype was traced to upregulation of multiple EGF
genes and downregulation of MAPK pathway components.
A similar approach to keratinocytes-specific deletion of TAF10 demonstrated
slightly altered requirements for this subunit relative to that of TAF4 (Indra et al. 2005).
Specifically, TAF10 is required for fetal epidermal differentiation, skin barrier formation,
and normal patterns of fetal skin gene expression, but dispensable for adult keratinocyte
homeostasis. Hence, adult epidermis lacking TAF10 showed normal gene expression
patterns, responses to UV irradiation, and proper regeneration after wounding. Recently,
the requirements of TAF10 in fetal liver development and adult homeostasis were
analyzed by targeted deletion of the same allele (Tatarakis et al. 2008). These studies
showed that TAF10 is required for the expression of most fetal hepatic genes and normal
liver organogenesis, and that its deletion disrupts normal TFIID complex assembly along
with general transcription factor promoter occupancy. Conversely, loss of TAF10 in
adult hepatocytes has no detectable adverse phenotypes, causes downregulation of only a
small subset of genes, and surprisingly derepresses genes that are normally silenced
neonatally. These observations led the authors to propose a multiclass gene model in
which some promoters require TFIID for their ongoing transcription, others are actively
repressed by TFIID occupancy, and the majority employ TFIID for the first round of fetal
transcription but continue to be activated in the adult despite its absence. New
conditional knockout models and novel approaches to in vivo TAF ablation, including
Chapter 1: Introduction 14
virally mediated RNA, will continue to enhance our understanding of TFIID’s function in
mammalian development and differentiation.
Embryonic and Neonatal Liver Development
The liver is unique to vertebrates and is responsible for many of the most critical
metabolic and homeostatic functions of adult organisms in addition to being required for
hematopoiesis during fetal and neonatal development. In the adult the liver is the
primary site of carbohydrate, lipid, and protein metabolism and storage. Additionally, it
is responsible for the synthesis and secretion of most serum proteins, including many
growth and coagulation factors and several digestive enzymes. Finally, the liver is a
critical site for the removal of endogenous waste products and exogenous toxins,
including most pharmaceuticals. Thus because of its central and varied role in
organismal function, there is great interest in understanding how the vertebrate liver
develops and is maintained (Zaret 2002; Zaret and Grompe 2008).
While the molecular mechanisms of liver organogenesis are not yet fully
understood, the morphogenetic steps of liver development have been well characterized.
At mouse embryonic day 6.5-7.5 or 15-16 in humans, the primitive streak forms anterior
to posterior along the ventral midline initiating gastrulation and leading to the creation of
the three germ layers (Figure 3). Of these the definitive endoderm results from
ingression of epiblast cells through anterior portions of the streak and eventually gives
rise to the organs of the embryonic gut including the liver, pancreas, lung, and thyroid; at
the same time the extra-embryonic visceral endoderm is displaced laterally (Lewis and
Chapter 1: Introduction 15
Tam 2006). Cell lineage experiments show that the hepatic endoderm arises soon after
gastrulation from lateral portions of the ventral foregut epithelium and a smaller group of
cells along the ventral midline epithelium, which are joined upon tube closure (Lawson et
al. 1991; Tremblay and Zaret 2005). As the hepatic endodermal cells rapidly proliferate,
they migrate into the neighboring septum transversum mesenchyme to form the liver bud,
which becomes increasingly vascularized and by embryonic day 10 develops the stromal
spaces that will eventually form the sinusoids of the adult liver. By embryonic day 9
these cells already express important early hepatic markers, including albumin (ALB), -
fetoprotein (AFP), and transthyretin (TTR) and are now considered hepatoblasts, the
bipotential progenitors that will differentiate into the major cell types of the adult liver
(Nobuyoshi Shiojiri1984; Germain et al. 1988; Gualdi et al. 1996). Hepatocytes
differentiate from hepatoblasts between embryonic day 14 and birth, and the neonatal
hepatocytes continue to proliferate and induce adult hepatic gene expression between
birth and neonatal day 21.
Hepatoblasts are small stem-like cells that are defined by their expression of both
hepatocyte and cholangiocyte markers and their ability to differentiate into both cell
types. They expand as a homogenous progenitor population in the liver bud until
embryonic day 14.5, when a subpopulation reduces its expression of hepatocyte genes
and differentiates towards the cholangiocyte or bile duct epithelial cell lineage; the
remaining hepatoblasts commit to the hepatocyte lineage between embryonic day 16 and
birth. Primary hepatoblasts can be reproducibly purified from mouse embryonic day 13.5
livers by enrichment of hepatoblast-specific markers including E-cadherin (CDH1) and
Chapter 1: Introduction 16
delta-like 1 (DLK), or depletion of the hematopoietic markers TER119 and CD45 (Nitou
et al. 2002; Tanimizu et al. 2003; Nava et al. 2005). Additionally human heptaoblasts
have been successfully purified and characterized by a variety of techniques, and shown
to expand and differentiate when transplanted to immunocompromised mice (Mahieu-
Caputo et al. 2004; Wauthier et al. 2008). Several groups have reported the ex vivo
culture of primary hepatoblasts and their faithful bipotential differentiation stimulated by
extracellular factors; in particular the interleukin-6 family member oncostatin M (OSM)
appears to be absolutely required for hepatocyte-specific differentiation (Kamiya et al.
1999; Kamiya et al. 2002). Further, immortalized hepatoblast cell lines that maintain
progenitor gene expression patterns and the ability to differentiate into cholangiocytes
and hepatocytes in vitro have been developed (Rogler 1997; Strick-Marchand and Weiss
2002; Tanimizu et al. 2004). Together these in vitro techniques have helped to elucidate
the signaling and transcriptional mechanisms of in vivo liver development (Strick-
Marchand et al. 2004; Tanimizu and Miyajima 2004; Ader et al. 2006). The extracellular
signaling events that lead to hepatic endoderm specification and hepatoblast commitment
have been extensively studied by tissue explant and gene knockout experiments. Hence,
hepatic fate decisions are initiated by suppression of Wnt and fibroblast growth factor 4
(FGF4) signaling in the foregut mesoderm and suppressed by active Wnt signaling in the
posterior gut mesoderm (Wells and Melton 2000). The hepatic endoderm’s anterior-
posterior position is further refined by retinoic acid signaling from the paraxial
mesoderm, and following tube closure, solidified by suppression of sonic hedgehog
(SHH) signaling in the dorsal endoderm (Apelqvist et al. 1997; Kumar et al. 2003).
Chapter 1: Introduction 17
Foregut hepatic differentiation is further stimulated by multiple FGFs secreted by the
cardiac mesoderm and bone morphogenetic proteins (BMPs) secreted by the septum
transversum mesenchyme (Jung et al. 1999; Rossi et al. 2001). While it is known that
specific extracellular signaling events alter intracellular mitogen-activated protein kinase
activity (MAPK) and cause tractable changes in cellular transcription factor expression
levels, the mechanism by which soluble factors transduce global transcription programs
to specify hepatoblast cell fate are not well understood (Wandzioch and Zaret 2009).
The transcriptional control of hepatic differentiation is currently attributed to a
large and dynamic network of liver-enriched classical sequence-specific activators
(Cereghini 1996; Costa et al. 2003). These proteins are categorized based on the
structural similarity of their DNA binding domains and include the onecut homeodomain
family (HNF-1), leucine zipper family (C/EBP), winged helix family (HNF-3/FOXA),
and nuclear hormone receptor family (HNF4, COUP-TFII,, LRH-1, FXR, PXR). While
these activators are widely detectable throughout multiple tissues and phases of liver
development, their onset and degree of expression correlates well with their unique
requirements in sequential phases of hepatic organogenesis (Kyrmizi et al. 2006). Hence,
the initial specification of hepatoblasts within the definitive endoderm requires HNF-3
and HNF-3 , which are expressed as early as gastrulation (Duncan et al. 1998; Lee et al.
2005). HNF-4 and GATA-6 are expressed in the developing hepatic endoderm and are
required for liver bud expansion and the hepatoblast to hepatocyte transition (Duncan et
al. 2000; Li et al. 2000; Zhao et al. 2005). HNF-1b and HNF-6 are first expressed in the
developing liver bud and are required for the lineage split of hepatoblasts to hepatocytes
Chapter 1: Introduction 18
and cholangiocytes (Clotman et al. 2002; Coffinier et al. 2002). Further, C/EBP , which
is first expressed at birth, is necessary for the expression of metabolic genes which will
function in the adult liver (Wang et al. 1995). The delicate spatial and temporal
regulation of liver-specific gene expression in both the developing tissue and the adult
organ is proposed to be achieved by the combinatorial activation and repression of each
unique promoter by this diverse toolbox of proteins; regulatory diversity is further
complicated by the ability of many of these factors to heterodimerize. Additionally, the
liver-enriched transcription factors have been shown to autoregulate their own and each
other’s expression throughout development and adult homeostasis (Odom et al. 2004;
Odom et al. 2006). While the circuitry of liver-enriched sequence-specific activators has
been extensively investigated, the role of core promoter recognition complexes, co-
activators, and chromatin remodelers in liver specification is remains to be understood.
Hepatic Regeneration
The liver is distinct among metazoan organs for it intrinsic regenerative ability
following acute physical, toxic, or viral injury (Fausto and Campbell 2003; Fausto et al.
2006). While much attention has been given to the potential role of resident liver stem
cells or oval cells in maintaining the chronically injured liver, the primary source of liver
regeneration in healthy animals is thought to be the limited proliferation of adult
hepatocytes (Figure 3). This unique regenerative capacity has made the liver a target of
human transplantation therapies as well as a model system for understanding adult stem
cell differentiation and organ plasticity.
Chapter 1: Introduction 19
Within 36-42 hours of partial hepectomy (PH), the most accepted experimental
model of hepatic injury, 95% of quiescent mouse hetapocytes synchronously transition
from G0 to G1 and enter S-phase to begin DNA replication (Grisham 1962; Mitchell and
Willenbring 2008). The hepatocytes divide once or twice and the full liver mass can be
restored within one to two weeks in rodents or approximately one to two months in
humans, although in most cases the original liver architecture is altered. Mouse models
of chronic liver injury suggest that adult hepatocytes have an even greater replicative
potential, which may allow for novel therapeutic applications. Hence, when wild type
hepatocytes are transplanted into urokinase plasminogen activaor (uPA) transgenic mice
they undergo up to 15 cell divisions almost fully replacing the necrotic host liver (Rhim
et al. 1994). Similarly, serial repopulation of the chronically injured fumarylacetoacetate
hydrolase (FAH) knockout mouse liver with wild type hepatocytes suggests that at least
80 rounds of division are possible (Overturf et al. 1996; Overturf et al. 1999).
Much like developing heptaoblasts, hepatocyte regeneration depends on a
complex network of extracellular signaling molecules and cellular transcription factors
(Fausto et al. 1995). Hence, within hours of hepatic injury nonparenchymal cell derived
tumor necrosis factor (TNF) and interleukin-6 (IL-6) stimulate the nuclear factor-kappa B
(NF B), signal transducer, and activator of transcription 3 (STAT3) pathways
respectively, inducing immediate early gene expression, promoting the G0 to G1
transition, and priming the quiescent growth factor immune hepatocytes for activation by
additional extracellular signals (Akerman et al. 1992; Webber et al. 1998; Iwai et al.
2001). Next mesenchyme derived hepatocyte growth factor (HGF) and hepatocyte
Chapter 1: Introduction 20
expressed transforming growth factor alpha (TGF ) activate the mitogen-activated
protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) cascades to promote
progression past the G1-S restriction point and induce expression of additional
transcription factors (Mead and Fausto 1989; Webber et al. 1993; Borowiak et al. 2004;
Huh et al. 2004). The activation of NFkB and STAT3 is the result of post translational
modifications and occurs independent of new protein synthesis, allowing these factors to
induce immediate early gene expression within hours of hepectomy (Cressman et al.
1994; Cressman et al. 1995). The activated immediate early genes include
transmembrane receptors required for continued mitogen responsiveness, cyclins and
cyclin dependent kinases which mediate cell cycle progression, and additional
transcription factors that drive the regenerative program (Mohn et al. 1991). Among
these transcription factors are known mitogen dependent cell cycle regulators not
normally expressed in the adult liver including c-Jun, c-Fos (AP-1), and c-Myc; the
overexpression or deletion of these genes has been shown to promote or impair liver
regeneration respectively (Thompson et al. 1986; Morello et al. 1990; Behrens et al.
2002). A second class of immediate early genes includes liver-enriched transcription
factors such as C/EBP which are responsible for the reestablishment of normal
hepatocytic function and coincident with these is an increase in the expression of liver
proteins such as albumin (ALB), 1-antitrypsin (AAT) and Phosphoenolpyruvate
contribute greatly to our understanding of hepatogenesis, and hasten the advancement of
therapeutic liver repopulation (Yamanaka 2007; Jaenisch and Young 2008). Intriguingly,
iPS cells have been successfully generated from adult hepatocytes suggesting that the
mature cell type possesses all but a few factors required for proliferation, and raising the
possibility that damaged liver cells could be dedifferentiated, modified, and transplanted
(Aoi et al. 2008). While iPS cells have not yet been differentiated into functioning
hepatocytes, they have been specifically differentiated to cardiomyocytes, adipocytes,
retinal cells, and multiple hematopoitic lineages (Schenke-Layland et al. 2008; Hirami et
Chapter 1: Introduction 25
al. 2009; Senju et al. 2009; Zhang et al. 2009). Furthermore, comparative studies suggest
that iPS cells can be differentiated by the same protocols and with similar efficiency as
ES cells (Taura et al. 2009). Importantly, directed in vivo differentiation of genetically
modified autologous iPS cells followed by transplantation has been used to correct mouse
models of human disease including sickle cell anemia, fanconi anaemia, and hearing loss
(Nishimura et al. 2009; Raya et al. 2009). Such experiments raise the possibility that a
patient’s own somatic cells could be used for therapeutic liver repopulation.
Understanding the transcriptional mechanisms of liver development, regeneration, and
dedifferentiation is essential to realizing this potential.
Chapter 1: Introduction 26
Figure 1: Model of Preinitiation Complex Assembly
Sequence-specific activators (green) bind proximal (PA) and distal (DA) enhancer
elements within a genes regulatory DNA and recruit TFIID (yellow) to the core promoter.
These activators and/or TFIID in turn recruit chromatin remodeling complexes such as
SWI/SNF (orange), coactivators including Mediator (MED, blue), and TFIIA and TFIIB
(purple). The TFIID/TFIIA/TFIIB heterotrimer sequentially recruits TFIIE, TFIIF, PolII
(red), and TFIIH (purple), allowing for promoter escape and productive transcriptional
elongation.
Chapter 1: Introduction 27
H
PETATA
TFIID
DE
MED
PolII
E
F
SWI/SNF
BA
Chapter 1: Introduction 28
Figure 2: Combinatorial Model of Core Promoter Recognition Complex Diversity
Canonical TFIID consisting of TBP (red) and 15 associated TAFs (yellow) is
believed to be present at most promoters and in most cell types. Additional regulatory
complexity comes from TBP-free TAF containing complexes such as TFTC which
contain some TAFs plus additional unique proteins (burgundy), TBP-Related Factor
complexes such as TAF3-TRF3 (green), and alternate forms of TFIID that use tissue-
specific TAFs such as TAF5b and TAF7l (blue). Novel, as yet unidentified complexes
may be present in specific tissues or developmental programs.
Chapter 1: Introduction 29
TAF3
-TR
F3M
yoge
nesi
s
TAF4
b-II
DFo
llicu
loge
nesi
s/Sp
erm
atog
enes
is
TFI
IA-T
RF2
TFT
C
TAF7
l-II
DSp
erm
ioge
nesi
s
Can
onic
al T
FIID
Chapter 1: Introduction 30
Figure 3: Hepatic Development and Regeneration
Hepatoblasts, the common bipotential liver progenitors, develop from the
definitive endoderm between embryonic day 8.5 and 13.5. Starting at embryonic day
14.5 they differentiate to cholangiocytes or bile duct epithelial cells and hepatocytes.
Hepatocytes continue to proliferate and mature from before birth until at least neonatal
day 21. Following acute liver injury, mature hepatocytes reenter the cell cycle to
regenerate liver mass and function. Rare resident liver stem cells, or oval cells, may also
expand and differentiate contributing to liver regeneration.
Chapter 1: Introduction 31
Hea
d
Para
xial
Mes
oder
m
Som
ites
Car
diac
Mes
oder
m
Hep
atic
End
oder
mD
orsa
l End
oder
m
Ven
tral
End
oder
m
Sept
um T
rans
vers
um
Hep
atob
last
sE
8.5-
E14
.5
Adu
lt C
hola
ngio
cyte
sO
val C
ells
Neo
nata
l Hep
atoc
ytes
Adu
lt H
epat
ocyt
es
Cyc
ling
Hep
atoc
ytesIn
jury
and
Reg
ener
atio
nFe
tal a
nd N
eona
tal D
evel
opm
ent
Chapter 1: Introduction 32
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Chapter 1: Introduction 40
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Zhou, J., Zwicker, J., Szymanski, P., Levine, M., and Tjian, R. 1998. TAFII mutations disrupt Dorsal activation in the Drosophila embryo. Proc Natl Acad Sci U S A 95(23): 13483-13488.
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration Summary
The precise spatial and temporal control of gene expression required for
organismal development and cellular differentiation is primarily determined at the level
of transcriptional regulation. Historically, diverse cellular programs of proliferation,
terminal differentiation, and specialized function have been attributed to a repertoire of
sequence-specific activators and repressors. General transcription factors including
coactivators such as Mediator and core promoter recognition factors such as TFIID were
assumed to be ubiquitous and invariant between tissues and developmental time points.
Recent work from a variety of model organisms and mammalian differentiation programs
supports an expanding role for TAF paralogs, TBP-related factors, and alternative core
promoter recognition complexes in determining tissue and developmental stage-specific
transcriptional programs. The vertebrate liver serves varied and critical functions in
metabolism, growth control, and detoxification; however, the precise transcriptional
mechanisms of hepatic development, differentiation, and regeneration remain elusive.
Herein, I examine the expression of TBP, TRFs, TAFs and other coactivators in adult
mouse tissues and purified liver cells. Furthermore, I demonstrate that during liver
development and hepatocyte commitment canonical TFIID is in toto eliminated and its
gene locus transcriptionally silenced coincident with retention of TRF3 expression.
Importantly, an in vitro model of hepatic development recapitulates these observations.
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
Introduction
The highly specific and exquisitely complex patterns of gene expression required
for organismal development and cellular differentiation have traditionally been attributed
to sequence-specific DNA binding activators, while the general transcription factors
including the core promoter recognition complex TFIID and the coactivator Mediator
were assumed to be invariant (Thomas and Chiang 2006). In the mammalian liver
developmental commitment and functional specialization are primarily attributed to a
large group of heterogeneous nuclear factors (HNFs) and other liver-enriched activators,
while changes in the basal machinery have remained largely uninvestigated (Schrem et
al. 2002). Recent advances in genetic, biochemical, and cell culture techniques have
allowed for a more thorough examination of core promoter recognition and coactivator
proteins in diverse cell types and differentiation programs.
The first indication that the canonical core promoter recognition complex TFIID
may not be essential at all developmental stages or for the transcription of all genes came
from multiple gene disruption studies. Hence, while depletion of TBP in the mouse or
zebrafish leads to eventual embryonic lethality it does not prevent the onset of zygotic
transcription or reduce RNA PolII activity at the earliest embryonic stages, suggesting
that an alternative mechanism of core promoter induction must take its place in this
particular setting (Muller et al. 2001; Martianov et al. 2002). Similarly, disruption of the
TBP associated factors TAF10 and TAF8 also led to eventual lethality but only after
expansion of the inner cell mass, and staining experiments suggest differing requirements
for these factors in the developing blastocyst (Voss et al. 2000; Mohan et al. 2003).
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
Conditional inactivation of the key TFIID subunit, TAF4 in embryonic fibroblasts
showed it to be nonessential for cellular growth and differentiation and required for the
transcription of many but not all fibroblastic genes, while depletion in developing
keratinocytes suggested that it is essential to epidermal differentiation and maintenance,
consistent with differential tissue-specific functions (Mengus et al. 2005). Intriguingly,
TAF10 is also required for embryonic keratinocyte development but unlike TAF4 is
dispensable for maintenance of the adult epidermis (Indra et al. 2005). Most recently,
TAF10 was shown to be required for embryonic liver development but dispensable for
the maintenance of adult hepatocytes and the ongoing expression of most liver-specific
genes, suggesting that an alternative mechanism of core promoter activation may replace
TFIID in the hepatogenic program (Tatarakis et al. 2008).
Additional evidence for tissue-specific differences in TFIID activity comes from
several limited observations of differences in TBP and TAF expression throughout adult
tissues. Hence, in an early study TBP and TAF12 expression were shown to vary widely
between adult mouse tissue, being highly enriched in the testes and nearly undetectable in
the heart and nervous system (Perletti et al. 1999). Furthermore, differences in TBP
abundance were inversely correlated with TRF levels suggesting that TRFs may partially
replace TBP in certain tissues. In another report, TAF4 was shown to be highly
upregulated during neuronal differentiation and required for the induction of adult
neuron-specific genes (Perletti et al. 1999). Furthermore, increased TAF8 (TBN)
expression was shown to occur during adipogenesis, and functional TAF8 shown to be
required for induction of the adipogenic gene expression program (Perletti et al. 1999).
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
Additionally, an investigation of the mouse TAF4 paralogue, TAF4b, demonstrated that
TAF4 is significantly donwregulated in the adult liver at least at the mRNA level
(Freiman et al. 2001). While it is important to note that many of these studies are
observational and may depend on the accuracy of specific reagents, collectively they
provide a precedent for the idea that significant differences do exist in the expression of
TFIID components between tissues and cell types.
The most recent indication of developmental stage-specific changes in the core
promoter recognition machinery occurs in the myogenic program. Hence, in both
primary cells and an in vitro model of myogenesis TBP and many TAFs are in toto
degraded and their mRNA levels significantly decreased during the transition from
myoblasts to myotubes (Deato and Tjian 2007). Importantly, levels of other general
transcription factors including TFIIA-H and RNA PolII are unchanged as are levels of
TAF3 and the TBP-related factor TRF3. Furthermore, TFIID was shown in vitro to be
dispensable for the activated transcription of the myoube-specific myogenin promoter,
suggesting that TBP and TAFs are at least in part functionally nonessential for the onset
and/or maintenance of transcription in the adult cell type (Deato et al. 2008).
Additionally, multiple components of the canonical coactivator complex mediator are
also significantly donwregulated during the myogenic transition, suggesting that like
TFIID, Med activity may vary significantly between developmental stages and tissues.
Importantly, downregulation of TFIID does not appear to be a hallmark of all
developmental transitions, as TBP and TAF levels are shown to be unaltered at both the
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
protein and mRNA level during the differentiation of mouse ES cells to motor neurons
(Francisco Herrera, personal communication).
Results
Varied Expression of TFIID Subunits in Diverse Mouse Tissues
The recent seminal finding that TFIID including TBP and many TAF subunits is
wholly degraded and replaced by a novel core promoter recognition complex consisting
of TRF3 and TAF3 during terminal differentiation has thus far been restricted to murine
muscle development (Deato and Tjian 2007). To better understand if this intriguing
transcriptional mechanism is unique to myogenesis or is a common feature of other
distinct differentiation programs we investigated the disposition of TBP and multiple
TAFs in diverse adult mouse tissues at both the mRNA and protein level.
To determine the relative levels of TBP and TAF protein in differentiated mouse
tissues we subjected whole tissue lystates to Western blot analysis with specific
antibodies against TBP, TRF3, TAF1, and TAF4 (Figure 1). Equal amounts of total
protein were analyzed and GAPDH was used as a loading control. Importantly, TBP and
multiple TAFs are enriched in proliferative C2C12 myoblasts and whole E13.5 embryos
which contain multiple progenitor cell types including myoblasts and hepatoblasts, but at
significantly reduced levels in differentiated C2C12 myotubes as previously reported.
Additionally, TFIID components are highly expressed in the testes and spleen which
poses significant stem and progenitor cell populations and were formerly shown to
contain high levels of TBP (Persengiev et al. 1996; Perletti et al. 1999). Intriguingly,
Chapter 2: TBP, TRFs, and TAFs in Liver Development and Regeneration
TBP, TAF1, and TAF4 protein appear to be all but absent from many adult tissues and at
exceedingly low levels in the whole liver; possibly at lower levels than in differentiated
myotubes. Conversely, TRF3 protein is as abundant in many adult tissues as it is in
C2C12 myoblasts or the whole embryo, and appears to be particularly abundant in the
1μM insulin, 2mM glutamine, 10ng/ml hepatocyte growth factor (Peprotech), and
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
20ng/ml Oncostatin M. After seven days RNA was harvested for reverse transcription
and qPCR with validated gene-specific primers.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 1: Expression of TRF3, TAF7l, and TAF13 in purified liver cells.
Recombinant TRF3, whole ovary lysate, adult liver lysate, hepatoblasts, and
hepatocytes were subjected to western blotting with mouse monoclonal antibody 58C9
and rabbit anti-TRF3 antibodies (A). Recombinant TAF7l, testes lysate, fetal and adult
liver lysate, hepatoblasts and hepatocytes were subjected to western blotting with two
different polyclonal anti-TAF7l antibodies (B). Hepatoblast and hepatocyte lysates were
subjected to western blotting with mouse anti-TAF13 antibody (C).
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
rTR
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B
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C
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 2: shRNA Mediated Depletion of TRF3, TAF7l, and TAF13 in HPPLs.
The pLKO.1 vector, which contains lentiviral 5’ and 3’ leader and other
regulatory sequences, expresses short hairpin RNAs from the human U6 promoter and
puromycin N-acetyl-transferase from the PKG promoter (A). Proliferating HPPLs were
infected for 24 hours with pLKO.1 viral supernatants expressing the indicated shRNA,
selected for four days with 1.5μg/ml Puromycin and knockdown assessed by qPCR (B).
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
5’ LTR 3’ LTRRRE cPPT PGK-PuroU6 shRNA
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 3: Expression of Adult Hepatic Genes in Differentiated and pLKO.1
Tranduced HPPLs.
Following four days of selection, five days post infection, HPPLs were
differentiated for five days in the presence of 20ng/ml Oncostatin M and the induction of
hepatic genes was analyzed by qPCR.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
020406080100
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 4: Chromatin Immunoprecipitation in Fetal and Adult Liver
E13.5 and adult livers were individually dissected, crosslinked, and chromatin
was immunoprecipitated with IgG or TRF3, TAF7l, and TAF13 antibodies. Crosslinking
was reversed and precipitated DNA was analyzed by qPCR. Signals were normalized to
input and expressed as fold enrichment over the IgG control.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
0
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 5: Chromatin Immunoprecipitation in Differentiated HPPLs.
Proliferating HPPLs were infected for 24 hours with pTRIPZ based lentivirus
expressing FLAG tagged TRF3, TAF7l or TAF13 and differentiated for five days in the
presence of 20 ng/ml Oncostatin M. Cells were crosslinked and chromatin was subjected
to immunoprecipitation with IgG or anti-FLAG polyclonal antibody. Crosslinking was
reversed and precipitated DNA analyzed by qPCR. Signals were normalized to input and
expressed as fold enrichment of the IgG control.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
0510152025
IgG
FL
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 6: Size Exclusion Chromatography of Adult Liver Nuclear Extract.
Adult mouse liver nuclear extract was fractionated on a Superdex-200 column and
fractions analyzed by western blot with TRF3, TAF7l, and TAF13 antibodies. Relative
molecular weights were calibrated with the standards in HMW and LMW Gel Filtration
Calibration Kit.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
0 1 2 3 4 5 6 7 8 9 10 11 12
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 7: Hepatic Differentiation of Human H9 ES Cells.
Human H9 ES cells were differentiated to mature hepatocyte-like cells by a three
stage protocol that mimics in vivo signaling events (A). Analysis of known marker genes
for ES cells, definitive endoderm, hepatoblasts, and mature hepatocytes by qPCR shows
that this protocol faithfully mimics human hepatogenesis (B).
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
110100
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hESC
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A B
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
Figure 8: Expression of TBP, TRFs, and TAFs in H9 Differentiation
Expression of TBP, TAF1, TAF3, TAF5, and MED17 as judged by qPCR,
remains stable during definitive endoderm and hepatoblast commitment, but decreases
significantly during hepatocyte maturation in the H9 system.
Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
0
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TBP TAF1 TAF3 TAF5 MED17
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
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Chapter 3: TRF3, TAF7l, and TAF13 in Hepatic Gene Regulation
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