(医学遗传学)15表观遗传学Epigenetics

表观遗传学Epigenetics谭理，副研究员复旦大学上海医学院生物医学研究院表观遗传学实验室&基础医学院细胞与遗传医学系12提

纲表观遗传学的历史表观遗传调控的主要机制表观遗传调控异常与疾病表观遗传药物的开发31.表观遗传学的历史GeneticsMendel+Morgan

+

Watson&ClickGene

Phenotype遗传学4GeneticcentraldogmaGenotypePhenotype

中心法则5GeneticscannotanswerallquestionsTwogeneticallyidenticalmalemonozygotictwins,raisedinthesameenvironment,manifestedverydifferentneurologicalfunctions.6(Korenkeetal.

Ann.Neurol.1996)Clonedanimalsgivedifferentcolor:

InCC,theorangecolorgenewasinactivatedinalloftheskincells—thusnoorangeinhercoat7ThebirthofCC

(CopyCat),theworld’sfirstclonedcat(TexasA&MUniversity,December22,2001)DonorCopy

CatABigGapbetweenGeneandPhenotypeGenome(Genotype)Phenotype1Phenotype2PhenotypeNEpigenome(Epigenotype)…GenotypeEpigenotype(s)Phenotype(s)表观遗传调控的重要作用8Epigeneticsisthestudyof“causalmechanisms”bywhich“thegenesofthegenotypebringaboutphenotypiceffects”.(Waddington1953)Nanney:cellswiththesamegenotypecouldhavedifferentphenotypesthatpersistedformanygenerations.Old

Epigenetics9GeneticsEpigeneticsThestudyofmitoticallyand/ormeioticallyheritablechangesingenefunctionthatcannotbeexplainedbychangesinDNAsequenceCurrent

Epigenetics10表观遗传

生物体不依赖于DNA序列变化的基因表达改变11表观遗传因子vs转录因子表观遗传学vs遗传学122.表观遗传调控的主要机制133000,000,000

base

pairIn10µmdiameternucleusEuchromatinv.s.HeterochromatinEuchromatin,or“active”chromatin,consistslargelyofcodingsequences,whichonlyaccountforasmallfraction(lessthan4%)ofthegenomeinmammalsAT-richDNAsequenceTranscriptionalfactoroccupancyAcetylationandH3K4methylationDynamicnatureHeterochromatin,or“locked-down”stateHistonedeacetylationMethylationofspecificlysineresidues(H3K9me3)Recruitmentofheterochromatin-associatedproteins(e.g.,HP1)EstablishmentofDNAmethylation14ChromatinremodelingcomplexesDNAmodificationsHistonemodificationscovalentposttranslationalmodificationsofprotrudingN-terminalhistonetails——“histonecode”

4.NoncodingRNAs

tRNA;rRNA;spliceosomalRNASmallnoncodingRNA:smallnucleolarRNA;microRNA;shortinterferingRNA;smalldouble-strandedRNALongnoncodingRNA5.

Post-transcriptional

epigenetic

regulation:

m6A主要调控方式15DNA甲基化16HowardCedar

(Hebrew

Univ)AharonRazin(Hebrew

Univ)AdrianBird(Univ

of

Edinburg)DNA去甲基化Anjana

RaoHarvad

Medical

School&UCSD17DNA甲基化的功能调节基因表达：基因转录起始位点、启动子、增强子区域的DNA甲基化通常导致DNA转录抑制直接改变转录因子与DNA顺式作用元件的结合募集DNA甲基化结合蛋白及转录沉默复合物

基因突变与染色体稳定性：CpG含量低于预期，进化过程中5mC容易突变DNA重复序列（非基因区域、转座子序列等）的CpG通常被甲基化

18胚胎着床前的DNA甲基化动态变化1.

OocyteTet3initiatesDNAdemethylationofpaternalDNAfrom

sperm2.The

function

of

Tet1

and

Tet2

in

blastocyst

development

remains

elusive19组蛋白乙酰化与去乙酰化DAVIDALLISRockefeller

University20组蛋白甲基化与去甲基化Yang

ShiHarvard

Medical

SchoolThomas

JenuweinUniversity

of

Vienna21Writer,

Reader,

and

EraserBothDNA

and

histone

modifications

are

reversibleand

instructive22非编码RNAAndrewFireStanford

UniversityCraigMelloUMSS23ENCODE计划“DNA元件百科全书”计划（Encyclopedia

of

DNA

Elements，简称ENCODE）

ENCODE发表了一系列重要文章，挑战了关于人类基因组的传统理论，即人类基因蓝图不是由孤立的基因和大量“垃圾DNA片段”组成的，而是一个复杂的网络系统，单个基因、调控元件以及与编码蛋白无关的其他类型的DNA序列一道，以交叠的方式相互作用，共同控制着人类的生理活动ECODE计划是继“人类基因组计划”后最大的国际合作计划之一，本质为“人类表观基因组计划”

24253.表观遗传调控异常与疾病Thefirstdefinitiveevidenceofaroleforepigeneticsinhumandiseasecameaboutaftertheunderstandingofgenomicimprintingandthefindingthatseveralgenesaresubjecttoregulationbythismechanism.(Reik.TrendsGenet.1989)Theepigenotypeshowsplasticityduringdevelopmentandpostnatally,dependingonenvironmentalfactorsandexperiences.Currently,

epigenetic

changes

could

be

detected

in

all

diseases

and

function

as

driving

force

or

regulatory

factors

261.基因印迹病Aformofepigeneticregulationinwhichtheexpressionofagenedependsonwhetheritisinheritedfromthemotherorthefather.Unequalexpressionofthematernalandpaternalallelesatanimprinteddiploidlocus.Uniparental

disomy(UDP,单亲源二体)

described

in

the

racetofind“Cysticfibrosis”gene

Prader-Willisyndrome(PWS;OMIM176270)

Angelmansyndrome(AS;OMIM105830)：5-to6-Mbdeletionin15q11-q1327InmostMendeliandisordersareusuallyidentifiedbyfindingmutationsineitherexonsorsplicesites,wherebythegeneproducts,RNAorproteins,arealteredornotproduced.Formanyofthesedisorders,however,thereisfrequentlyasmallgroupofpatientsinwhommutationscannotbeidentified

despitelinkagetothespecificlocus

FragileXsyndrome(OMIM309550)：XchromosomelinkageExpansionofanunstablenoncodingCGGrepeat(Warren2001)Change

in

gene

expression

dosage

(Quantitative

Biology)282.表观遗传调控因子异常导致疾病Genes

coding

epigenetic

regulators(enzyme/reader)

are

mutation

hotspotsManydisordersthemselvesdonothaveepigeneticmutationsbutalterchromatinstatesthatarecriticalcomponentsoftheepigenotype.CBP,MeCP2,DNMT3B,MTHFRRubinstein-Taybisyndrome(RSTS;OMIM180849)CREBBPorCBP29TET2突变与血液系统恶性肿瘤AML与CMML病人中TET2突变Tet2基因敲除小鼠在成年后自发MDS与CMML30Tet2基因敲除小鼠PhenocopyCMMLTable1.SummaryofthephenotypesofTetgenesknockoutmicePre-implantationdevelopmentPost-implantationdevelopmentPost-nataldevelopmentTet1-/-(Dawlatyetal.,2011)NormalSmallerbodysizeSmallerbodysizeTet2-/-(Quivoronetal.,2011;Moran-Crusioetal.,2011;Koetal.,2011;Lietal.,2011)NormalNormalSpontaneousmyeloidleukemiaTet3-/-

Tet3mat-/pat+(Guetal.,2011)Normal(AbnormalityinpaternalDNAdemethylation)MultipleorganabnormalityNeonatallethalityTet1:

Adult

learning

and

recognition

abilityTet2:

Adult

hematopoietic

stability,

ischemia

reperfusioninjuryTet3:

Unknown

(conditional

knockout)313.环境因素对表观基因组的影响Diet

(nutrients)andepigenotypesinaginganddiseaseAnage-dependentdecreaseofglobalDNAmethylation;Roleofdietasacontributingfactorincontrollingglobalmethylationstatus;FolateandB12deficienciesinsporadicneuropsychiatricdisordersSAMsupplementationinfoodHungry

and

CREarlyexperiences(behavior)andepigenotype

FrequentlickingandgroomingbyratmothersalteredtheDNAmethylationstatusinthepromoterregionoftheglucocorticoidreceptor(GR)geneinthehippocampusoftheirpups.(Weaveretal.

Nat.Neurosci.2004)Other

environmental

factors324.表观遗传药物的开发331.

Drugs

targeting

“Writer”DNMT（DNA甲基转移酶）抑制剂－－地西他滨：骨髓增生异常综合症（MDS）等EZH2（H3K27甲基转移酶）抑制剂：ALL、肺癌等DOT1L（H3K79甲基转移酶）抑制剂：AML342.

Drugs

targeting

“Eraser”HDAC抑制剂西达