Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer...
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Transcript of 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 InstituteCenter for Cancer Research
Laboratory of Population Genetics
April 21, 2011
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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
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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.
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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
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Chromatin and DNA Methylation
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5-methylcytosine
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DNA Methylation and Methyl Transferase
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Effects of DNA Methylation on Chromatin and Transcription
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Interaction between DNA Methylation and Chromatin
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Examples of Epigenetic Phenomena
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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
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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.
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Beckwith-Wiedemann Syndrome (BWS)
Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma.
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P57KIP2 Mutation in Beckwith-Wiedemann Syndrome (BWS)
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Loss of Imprinting (LOI) of A Regulatory RNA in BWS
mat
pat
N* BB 6 kb4.2 kb
mat patepigenotype
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Beckwith-Wiedemann syndrome (BWS)
mat
pat
pat
pat
mat
pat
mat
pat
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Loss of Imprinting (LOI) in Cancer
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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
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Allelic-specific Chromatin State Determined By ChIP-on-chip Method
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Inheritance Analysis Of Allelic Histone H3 Acetylation State
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Allelic-specific DNA Methylation
Kerkel et al, 2008
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Heritable Germline Epimutation of MSH2 in a HNPCC Family
Chan et al., 2006
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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
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How Epigenetics Affects Genetics?
Part 2
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Multistage Cancer Progression Model
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Distribution of CpG Sites in Human Genome
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Distribution of Methylation at CpG Sites in Human Genome
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Methylation of Human Chromosomes
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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
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High-throughput DNA Methylation Profiling UsingUniversal Bead Arrays
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Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome
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Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome
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MethylScope Array (McrBC)
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HpaII Enrichment by Ligation-mediated PCR (HELP)
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DNA Methylation Profiling of Human Chromosomes 6, 20 and 22
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DNA Methylation Profiling of Human Chromosomes 6, 20 and 22
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Comparison of Sequencing-based Methods to Profile DNA Methylation
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Comparison of Sequencing-based Methods to Profile DNA Methylation