Epigenetics

Introduction

Epigenetic machinery –General Mechanism DNA Methylation Histone Modification –Post translational Small Non coding RNA (mi RNA) Biogenesis.

Epigenetic changes –Cause (or) Consequence of Cancer Histone modification in Cancer Mi RNAs in Cancer

Factors -External & Internal ,Governs Epigenetics alterations Ageing Lifestyle Environment Factors.

Clinical application Diagnostic & Prognostic tool Epigenetic therapy

Methods of studying Epigenetic changes

Conclusion .

Definition : It refers to change (Heritable ) in gene expression ,which is not brought by

bringing change in DNA alphabets ,Indeed by other mechanism that provide extra layer of transcriptional control –Hence the name Epi (Greek i-over ,above, outer)-genetics.

First Introduced by C.H Waddington (1939) -coined to describe “Phenotype from Genotype”

? Monozygotic twins & cloned animal –Identical DNA ,shows difference in disease susceptibility and longevity.

? Getting older –Acquiring age related disease .? Food –Some cause health problem ,and others make Healthy .

! Unlocking the secrets behind these question can be done by “EPIGENETICS”

DNA Methylation DNMT1 DNMT3a & DNMT3b CpG Islands. Transcription factor & Poly II.

SAMSAM

HATs 2 groups : HDAC 2 groups:

Why non Histone proteins has to be asetylated?

Histone methylation H3k9 and H3k4.

Abberant DNA . Tumorigenesis (Oncogene & Tumor suppresor). Gastric & Colorectal – Hypermethylation frequency

& genetic mutation .

Retinoblastoma Rb gene . Renal cancer VHL CDKN2A /P16 –Bladder cancer LMLH1 –colon cancer .

DNA repetitive elements Specific gene promoters. Normally silenced gene –Antiapoptotic

growth promoting Mechanism –unknown

Where & what ? Acetylation & Methylation (H3k9 & H3k4) H4 Modification (Liver & Breast ) H3 (Prostate Marker –High risk of recurrence) Expression pattern Normal /cancerous Leukemia: 11q23 translocation MLL1 APL :T (15:17 ) PML RARα CBP/300 & E1A.

As an Oncogene :* miR 21: Breast cancer ,Breast tissue Topomysin(TPM1) & Programmed

cell death 4 . * miR17-92 : Lung cancer ,lung tissue (E2f1) E2f controversy (will see it later ) As Tumor suppressor :* miR 15a & miR 16-1 ,Bcl 2 * CML -15a is /Deleted = Bcl2* miR 101 EZH2

• As tumor suppressor & Oncogene . As Tumor suppressor miR29a, CLL .TCL (TCL-1 Oncoprotein ) & Lung Cancer (DNMT3a

& DNMT3b) –FHIT & WWOX (Tumor suppressor )• Oncogene in AML. miR29a converts myeloid progenitor to leukemic stem cell for

development of AML

Ageing :* Gametogenesis ,embryonic development ,life span .* Somatic cell –global ,Promoter .* RASSF1A-Breast tissue *ER gene –Colon tissue .*DBC1 –Bladder tissue + Translational cell ca. Life style :*Nutrients –Supply & regenerate *Chronic deficiency- SAM:SAH, reduction.*Lipotropes ,folate ,choline ,methionine ,vit B12,vit B6,riboflavin .

Environmental factors :*Tobacco smoke –Lung cancer .Tumor suppressor gene .*Synuclein –gamma .spreading of tumor .*Alcohol ,arsenic ,asbestos –ch3 gene ,inactivation .(Bladder ,head and Neck &

Squamous cell carcinoma ,mesothelioma ).

• Risk assessment * P16 & MGMT-sputum,Lung cancer .(Hypermethylated ) * IGF2-colorectal tissue ,colorectal cancer. (Hypermethylated )• Diagnosis : * GST1-Prostate cancer .(Hypermethylated ) * Vimentin –stool sampl,colon cancer.(Hypermethylated )• Prognosis & Response : * RASSF1A-poor prognosis (Breast ,Lung ,prostate) * E-cadherin –Metastatic potential. * miR-155 & Let-7miRNA –disease aggressive ,Indolent &

Survival (Surgery ) . * MGMT hypermethylated gene –Increase sensitivity

(Gliblastoma)Alkylating agent -Temozolomide .

Two classes of Drug approved FDA:

1. DNA Methylation Inhibitor (DNMT i)2. HDAC inhibitor :(HDAC i) * DNMT i – 5 azacytidine (Azacytidine ),5-aza-2’-deoxycytidine

(Decitabine),cytidine analogue (Zebularine),Antiarrythmic procainamide ,SGI-1027,RG108, MG98.

E.g : P15INK4B-MDS ,AML . * HDAC i- Sodium phenylbutyrate,sodium butyrate valporic acid ,Trichostain

A,Vorinostat,Panobinostat ,SAHA (Suberoylamide Hydroxamic acid),Depsipeptide (Romidepsin).

E.g: CDKN1A gene –P21 Cell cycle inhibitor Antiangiogenesis –Trichostatin ,SAHA ,Valporic acid .

Global Hypomethylation –Carcinogenic effect Lack of specificity Drug resistance by Unknown mechanism Problem in drug delivery:hENT1, hENT2

(Transporter),DCK(Phosphorylation) Decitabine,UCK (Phosphorylation) Azacytidine , CDA (catabolism)

The 5th & 6th alphabet (5mC & HmC),is no longer used in English words that’s its fate, But when miswritten (or)misspelled it change the Fate of an Individual .