Beruflich Dokumente
Kultur Dokumente
Epigenetics
WhatisEpigenetics
Definition heritabletraitsthatdonotinvolve changestotheunderlyingDNAsequence. h t th d l i DNA Epigenetic canbeusedtodescribeanyaspect otherthanDNAsequencethatinfluencesthe developmentofanorganism.
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Epigeneticsandtheenvironment
Genomicvs Epigenomic
Leadstoproblemsingeneticscreening
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Typesofepigenetics
HistoneModifications DNAMethylation MicroRNAs,smallinterferingRNAs,RNA interference Polycomb groupsilencing Hox genes
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Histonesmodifiers
HATcomplexes(histoneacetyltransferases) HDACcomplexes(histonedeacetylases) HDAC complexes (histone deacetylases) HTMcomplexes(histonemethyltransferases) HDMcomplexes(histonedemethylases) histoneser\thr proteinkinases (histonephosphorylation) histoneproteinphosphatases (dephosphorylate histoneser& thr)
HistoneModifications
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DefectsinH3,H4modificationscan haveimportantimplicationsinthe development ofvariouscancers becausecorrectregulationof heterochromatinandeuchromatin isdisrupted. Regionsofheterochromatinbecome demethylated andconvertedto euchromatin andregionsof euchromatin becomemethylated whichleadstogene inactivation.
Whichhistonemodificationismostimportant ingenetranscriptionregulation?
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DNA Methylation is the addition of a methyl group (M) to the DNA base cytosine (C) in a DNA methylation is the addition ofCpG sequence (M) to the DNA a methyl group DNA methylation y base cytosine i a C G sequence b t i in CpG
MethylationMutation
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Imprinting
Genesexpressionwhichisdictatedby maternalorpaternalDNA. t l t l DNA 50knownimprintedgenes Mostmaternal MostdirectedbyDNAmethylation,someby histonemodification histone modification
ProblemswithImprinting
p paternalimprinting,theresultisPraderWilli syndrome p g, y (characterised byhypotonia,obesity,andhypogonadism
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PronuclearMethylationAfterFertilization
G1SS
Cyclophosphamide treatedmalerats
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XchromosomeInactivation
Xic:Xinactivationcontrolcenter(~100kb) Xist andTsix aretranscribedtoyieldnon codingmRNAswhichareantisensetoeach other
CTCF
Atfertilization,theXist/Tsix locushasH3K9 onthematernalX At fertili ation the Xist/Tsix locus has H3 K9M on the maternal X chromosome. H3K9methylationkeepsthisregionsilent. PaternalXchromosomeisunmodified,allowingexpressionofXist RNA
Xist RNA"coats"theparental Xchromosomeincis atXic (viaRNA/DNAbp ?). Xist notexpressedonmaternal Xchromosome. H3K9M hasbeenreplacedbyH3K4M andsubsequentacetylation(H3K9Ac)on thematernal Xchromosome.Thelocusispoised,butnotexpressed.
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Thematernal Xchromosomenowhasactiveeuchromatin atXist/Tsix locus. ThisallowsbindingofCTCFandTsix transcription.ThisantisenseRNAblocks Xist transcription. maternal XchromosomedoesnotexpressXist ThispreventsXist RNAfromblockingtheXic domainonmaternal Xchromosome. *ResistanceofmaternalXchromosometoinactivationappearstodependon this. H3K273M recruitsasecondremodelingcomplexthatreplacesH2AwithH2A.1 varient,ahistonevarient commonlyfoundinconstitutiveheterochromatin.
H3K273M isfollowedbyH3K93M andsubsequentcreationofheterochromatinatpaternal Xic domain. HeterochromatinisinitiatedbyXist expression,butisthenpropagatedthroughoutthe parentalXchromosomevianucleosomes whichhaveincorporatedmacroH2A.1andDNA CMpG methylation. Eventuallyalmosttheentirechromosomeistranscriptionaly silenced. **Thisstateistheninheritedepigenetically. Duringlaterdevelopmentalstages,the"embryoproper"differentiatesfromtheinner massoftheblastocyst. Theearlypaternal imprintingprogramislostandXinactivationmustbereset.
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Summary
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