Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer...

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Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011

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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.

Transcript of Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer...

Page 1: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Epigenetics: from Inheritance to Cancer

Maxwell Lee

National Cancer InstituteCenter for Cancer Research

Laboratory of Population Genetics

April 21, 2011

Page 2: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center 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

Page 3: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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.

Page 4: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center 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

•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

Page 5: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Chromatin and DNA Methylation

Page 6: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

5-methylcytosine

Page 7: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

DNA Methylation and Methyl Transferase

Page 8: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Effects of DNA Methylation on Chromatin and Transcription

Page 9: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Interaction between DNA Methylation and Chromatin

Page 10: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Examples of Epigenetic Phenomena

Page 11: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Multiple Layers of Epigenetic Information

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

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Genomic Imprinting

Gynogeneticlethal

Androgeneticlethal

normal

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Igf2 Phenotype is Paternally Transmitted

Page 14: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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.

Page 15: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Beckwith-Wiedemann Syndrome (BWS)

Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma.

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P57KIP2 Mutation in Beckwith-Wiedemann Syndrome (BWS)

Page 17: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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

mat

pat

N* BB 6 kb4.2 kb

mat patepigenotype

Page 18: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Beckwith-Wiedemann syndrome (BWS)

mat

pat

pat

pat

mat

pat

mat

pat

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Loss of Imprinting (LOI) in Cancer

Page 20: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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

Page 21: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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

Page 22: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Inheritance Analysis Of Allelic Histone H3 Acetylation State

Page 23: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Allelic-specific DNA Methylation

Kerkel et al, 2008

Page 24: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Heritable Germline Epimutation of MSH2 in a HNPCC Family

Chan et al., 2006

Page 25: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.
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Heritable Epimutation of MSH2 in HNPCC due to Deletion of the 3’ Exons of TACSTD1

Ligtenberg et al., 2009

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Extension to Knudson’s Two-hits Hypothesis

Part 2

Epigenetic silencing

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Epigenetic Silencing of Tumor Suppressor Genes in Human Cancer

Part 2

Page 31: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

How Epigenetics Affects Genetics?

Part 2

Page 32: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Multistage Cancer Progression Model

Page 33: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Distribution of CpG Sites in Human Genome

Page 34: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Distribution of Methylation at CpG Sites in Human Genome

Page 35: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Methylation of Human Chromosomes

Page 36: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Common Methods Used in DNA Methylome Studies

Bisulfite-treated DNA

genomic DNA

Sequencing

Illumina

MSO microarry

MeDIP

McrBC

Hpa II enrichment

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High-throughput DNA Methylation Profiling UsingUniversal Bead Arrays

Page 38: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

High-throughput DNA Methylation Profiling UsingUniversal Bead Arrays

Page 39: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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

Page 40: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

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

Page 41: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

MethylScope Array (McrBC)

Page 42: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

HpaII Enrichment by Ligation-mediated PCR (HELP)

Page 43: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

Page 44: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

Page 45: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Comparison of Sequencing-based Methods to Profile DNA Methylation

Page 46: Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011.

Comparison of Sequencing-based Methods to Profile DNA Methylation