肿瘤的表观遗传调控ppt课件.ppt

肿瘤的表观遗传调控(EpigeneticRegulationofCancer)Chromatinpackaging表观遗传学概念Cancerepigenetics5EnzymaticmethylationoftheC–5positionofcytosineresiduescaneffectepigeneticinheritancebyalteringtheexpressionofgenesandbytransmissionofDNA
methylationpatternsthroughcelldivision.
Thus,inadditiontoitswell–knownroleindeamination
mutationalhotspotsinhumanDNA,DNAmethylation
maycontributetogeneinactivationincancer.10哺乳动物基因组中5mC占胞嘧啶总量的2%-7%，约70%的5mC存在于CpG二连核苷。
在结构基因的5’端调控区域,CpG二连核苷常常以成簇串联形式排列，这种富含CpG二连核苷的区域称为CpG岛(CpGislands)，其大小为500-1000bp，约56%的编码基因含该结构。
基因调控元件(如启动子)所含CpG岛中的5mC会阻碍转录因子复合体与DNA的结合。
DNA甲基化一般与基因沉默相关联；
非甲基化一般与基因的活化相关联；
而去甲基化往往与一个沉默基因的重新激活相关联。癌细胞的整个基因组水平处于低甲基化状态，比正常低20%～60%，这种低甲基化大多发生于编码区和内含子区域，以及约占人类基因组20%～30%的重复序列区

抑癌基因启动子区域CpG岛高度甲基化，且与DNA结合的组蛋白广泛去乙酰化
Genesilencing
DNAmethylationisapowerfulmechanismforthe
suppressionofgeneactivity.
Thereisreciprocalrelationshipbetweenthe
densityofmethylatedcytosineresiduesandthe
transcriptionalactivityofagene.
Themethylgroupsdonotaffectbase
pairingbutcaninfluenceprotein–DNA
interactionsbyprotrudingintothemajorgroove.●Thestrongeffectof5–methylcytosine(5mC)inmammalianpromoterregionssuggeststhatDNAmethylationinhibitstranscriptionbyinterferingwithtranscriptioninitiation.
●DNAmethylationreducesthebindingaffinityofsequence–specifictranscriptionfactors.
●Methylation–dependent,sequence–specificDNA–binding
proteins,suchasMDBPmayactastranscriptional
repressors.组蛋白修饰Histonemodifications—includingacetylation,
methylationandphosphorylation—areimportantintranscriptionalregulationandmanyarestablymaintainedduringcelldivision,althoughthemechanismforthisepigeneticinheritanceisnotyetwellunderstood.ProteinsthatmediatethesemodificationsareoftenassociatedwithinthesamecomplexesasthosethatregulateDNAmethylation.Covalentmodificationofhistones:
Acetylationoflysines
Methylationoflysinesandarginines
PhosphorylationsofserinesandthreoninesHistones
•5types:
H2A,H2B(slightlylysrich),
H3,
H4(argrich)
H1(lysrich).Allrelativelysmallproteins.
•Per200bpofDNA:2moleculeseachofH2A,H2B,H