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Epigenetics: - Epi'genetics - On' or Over' The Genetic Information Encoded in The DNA

This document discusses epigenetics, which is the study of reversible heritable changes in gene function and expression that occur without changes in the DNA sequence. It provides examples of epigenetic mechanisms such as DNA methylation and histone modifications. These epigenetic marks can be influenced by the environment and affect gene expression. Epigenetic changes also play a role in disease development, including cancer formation, by regulating which genes are turned on or off. The document then focuses on estrogen signaling in breast cancer and how estrogen stimulation induces dynamic epigenetic changes and gene regulation in responsive gene promoters.

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312 views14 pages

Epigenetics: - Epi'genetics - On' or Over' The Genetic Information Encoded in The DNA

This document discusses epigenetics, which is the study of reversible heritable changes in gene function and expression that occur without changes in the DNA sequence. It provides examples of epigenetic mechanisms such as DNA methylation and histone modifications. These epigenetic marks can be influenced by the environment and affect gene expression. Epigenetic changes also play a role in disease development, including cancer formation, by regulating which genes are turned on or off. The document then focuses on estrogen signaling in breast cancer and how estrogen stimulation induces dynamic epigenetic changes and gene regulation in responsive gene promoters.

Uploaded by

lordniklaus
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPT, PDF, TXT or read online on Scribd

Epigenetics

Epigenetics - On or over the genetic information encoded in the DNA

Epigenetics
The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next

Epigenetics and Different Aspects of Life


Development of multicellular organism Environment-organism interaction
For examples: Nutrition supplements and environmental toxins

Image: Randy Jirtle

Pathogenesis of diseases

Molecular Mechanisms that Mediate Epigenetic Phenomena


DNA methylation (CpG dinucleotides) Histone modifications

Nucleosome

Histone Modifications

Adapted from Lund and Lohuizen Genes Dev 2004

Epigenetic Regulation of Gene Expression


Epigenetic information modulates gene expression without modifying actual DNA sequence Histone modifications change the chromatin structure and affect the accessibility of DNA to regulatory proteins

Epigenetic Regulation of Gene Expression

Methylated DNA Histone

Histone Modification Status Correlates with Transcriptional Activity

Gene activation correlated with H3-K9 acetylation Gene silencing associated with H3-K9 methylation

Epigenetic Inheritance
Transmission of non-DNA sequence information through either meiosis or mitosis When a methylated DNA sequence replicates, only one strand of the next-generation double helix has all its methyl markers intact; the other strand needs to be remethylated Maintenance methylase theory
DNA methyltransferases (DNMTs): Enzymes that bind methyl groups to cytosine nucleotides DNMTs bind methyl groups to the naked cytosines based on the methylation template provided by the other strand-

Epigenetics and Cancer


Chromosomal infrastructure is essential for gene control, determining both active and repressed states It is important not only to turn the right genes on but also to turn the right genes off Histones and chromatin components have key roles in this decision making process If as few as three inappropriate genes are turned off, a normal cell can be converted into a cancer cell This epigenetic silencing of genes underlies a new approach to cancer therapy Mistargeting of these enzymes leads to tumorigenesis, but inhibition of their activity presents a novel approach to therapy

Estrogen and Breast Cancer


Estrogen receptor (ER) mediate estrogen signaling in various target tissues, including reproductive, bone, cardiovascular and central nervous system Critical role in breast cancer genesis and progression

Nuclear hormone receptor Ligand-dependent transcription factor

Chromatin Immunoprecipitation Microarray


Crosslink and sonicate

Immunoprecipitate with specific antibody

IP

Input

Label with fluorescent dyes

Co-hybridize onto CpG 12K array

Antibody Chromatin and/or Transcriptional Factors

Cy5 Labeled Targets Cy3 Labeled Targets

Agilent 185K oligonucleotide tiling array

Estrogen Stimulation Induces Dynamic and Concerted ER Binding and Histone Modifications in Responsive Promoters
ER

Ac-H3-K9
0 3 12 24 (hr)

diMe-H3-K9
0 3 12 24 (hr) 0

Ac/Me
3 12 24 (hr)
C20orf172 LOC153364 WBP11 VDP SIX2 LOC399818 SAMHD1 c-MYC MEA LACTB2 THAP8 HK2 KIS TCF4 THBS1 HSMPP8 C6orf170 C12orf10 KIAA1539 TTBK1 MTPN ATXN2L ZFY DLX1 APLP1 SLC30A1 RBBP8 TRIM8 STX5A CDC7 NEK1 OXA1L GABPB-2 C6orf148 CR2 MANEA CCND1 FAM46B SYVN1 FBXO15 RFXANK TPCN1 FOXD3 ENSG00000189238 RAB33A RCC2 USP48 TBC1D7 PIAS2 TGF-beta2 LOC344191 DKFZP434C131 HMX1 OTOP3 BHLHB5 CRABP1 NUP133 BCL2L11 CSDA GLT25D1 SIX1 C19orf15 FANCF C2orf13 PAFAH1B1 C10orf48 OPA3 LRP1 JMJD3 C9orf68 NEIL1 USP45 TOP3A TIA1 SKIP FLI1 DLL1 ADD2 BTF MGC14595 BLZF1 PTPN13 BCL11A ADAMTS5 ZNF143 ERCC6 LPAL2 MCART1 BC022085 FLJ45995 PCDH9 LOC441762

E2

0 3 12 24 (hr)

-3.0 Log2 ratio

+3.0

Activated Targets

92 putative ER target genes

Repressed Targets

Estrogen Receptor Binding on Promoter Regions

12 10 8 6 4 2 0
29383000 29383500 29384000 29384500 29385000 29385500 29386000 29386500

300

250

Fold enrichment

Fold enrichment

200

150

100

50

0 91678300 91678400 91678500 91678600 91678700 91678800 91678900 91679000 91679100

Chromosomal location (chr1)

Chromosomal position (chr1)

PTPRU

CDC7

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