Epigenetics: from Inheritance to Cancer

Maxwell Lee

National Cancer InstituteCenter for Cancer Research

Laboratory of Population Genetics

April 21, 2011

Definitions of Epigenetic and Epigenetics•Epigenetic is related to epigenesis---The theory that an individual is developed by successive differentiation of an egg rather than by a simple enlarging of a preformed entity.

•Epigenetics = epigenesis + genetics---developmental processes that initiated by genotype but don’t involve changes in genetic materials. By Conrad Waddington

Dualism of Genetic and Epigenetic Inheritance systems

•Genetics---Genetic inheritance vs. mutation, which operate on individuals to change DNA sequences in the spaces of evolution, population, and pedigree.

•Epigenetics---Cellular memory vs. plasticity, which operate on cells to change epigenetic states in the spaces of development, differentiation, and physiology.

Definitions of Epigenetic and Epigenetics

•Epigenetic is related to epigenesis---the theory that an individual is developed by successive differentiation of an egg rather than by a simple enlarging of a preformed entity.

•Epigenetics = epigenesis + genetics---developmental processes that initiated by genotype but don’t involve changes in genetic materials. By Conrad Waddington

•Epigenetics---the study of mitotically and/or meiotically heritable changes in gene function that can not be explained by changes in DNA sequences.

•Biochemical basis of epigenetics---DNA methylation and chromatin structure/modifications.

•Function of epigenetics---gene expression regulation.

Modern Definition of Epigenetics

Chromatin and DNA Methylation

5-methylcytosine

DNA Methylation and Methyl Transferase

Effects of DNA Methylation on Chromatin and Transcription

Interaction between DNA Methylation and Chromatin

Examples of Epigenetic Phenomena

Multiple Layers of Epigenetic Information

•Epigenetic information at the organism level•Epigenetic information at the cellular level•Epigenetic information at the allelic level

Genomic Imprinting

Gynogeneticlethal

Androgeneticlethal

normal

Igf2 Phenotype is Paternally Transmitted

Beckwith-Wiedemann syndrome (BWS)

•The cardinal features of this disorder are exomphalos, macroglossia, and gigantism in the neonate. •Patients have enlarged tongue, together with omphalocele or other umbilical abnormalities. Visceromegaly, adrenocortical cytomegaly, and dysplasia of the renal medulla are conspicuous features. •Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma occur with increased frequency.

•BWS is caused by mutation in P57KIP2 and LOI of LIT1 and IGF2.

Beckwith-Wiedemann Syndrome (BWS)

Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma.

P57KIP2 Mutation in Beckwith-Wiedemann Syndrome (BWS)

Loss of Imprinting (LOI) of A Regulatory RNA in BWS

mat

pat

N* BB 6 kb4.2 kb

mat patepigenotype

Beckwith-Wiedemann syndrome (BWS)

mat

pat

pat

pat

mat

pat

mat

pat

Loss of Imprinting (LOI) in Cancer

Epigenetics and Allelic Variation in Chromatin

5mCH3K9-Me

H3-Ac

Inactive

Active RNA

X inactivation and genomic imprinting

TF Pol II

Repressor

Inter-individual and intra-individual variation

Allelic-specific Chromatin State Determined By ChIP-on-chip Method

Inheritance Analysis Of Allelic Histone H3 Acetylation State

Allelic-specific DNA Methylation

Kerkel et al, 2008

Heritable Germline Epimutation of MSH2 in a HNPCC Family

Chan et al., 2006

Heritable Epimutation of MSH2 in HNPCC due to Deletion of the 3’ Exons of TACSTD1

Ligtenberg et al., 2009

Extension to Knudson’s Two-hits Hypothesis

Part 2

Epigenetic silencing

Epigenetic Silencing of Tumor Suppressor Genes in Human Cancer

Part 2

How Epigenetics Affects Genetics?

Part 2

Multistage Cancer Progression Model

Distribution of CpG Sites in Human Genome

Distribution of Methylation at CpG Sites in Human Genome

Methylation of Human Chromosomes

Common Methods Used in DNA Methylome Studies

Bisulfite-treated DNA

genomic DNA

Sequencing

Illumina

MSO microarry

MeDIP

McrBC

Hpa II enrichment

High-throughput DNA Methylation Profiling UsingUniversal Bead Arrays

High-throughput DNA Methylation Profiling UsingUniversal Bead Arrays

Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome

Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome

MethylScope Array (McrBC)

HpaII Enrichment by Ligation-mediated PCR (HELP)

DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

Comparison of Sequencing-based Methods to Profile DNA Methylation

Comparison of Sequencing-based Methods to Profile DNA Methylation