1、资料仅供参考,不当之处，请联系改正。什么是表观遗传？2.表观遗传是研究什么的？3.表观遗传和传统的遗传是什么关系？4.基因表达的转录调控资料仅供参考,不当之处，请联系改正。小结表观遗传的主要形式是：DNA methylation,histone modifications,and non-coding RNAs表观遗传与遗传的关系：。直接修饰而控制基因表达。通过修饰组蛋白来调节染色体的重塑来控制基因表达。ncRNAs 降解mRNA 或者阻断mRNA的翻译遗传（）是根本，表观遗传是通过调控基因的表达来显示它的作用的，是对中心法则的重要补充。意义：表观遗传的异常，会导致基因的异常表达，导致染色体的
2、结构的改变，从而导致错综负责的各类疾病。与突变不同，许多表观遗传修饰是可逆的，这就为疾病的治疗带来乐观的前景资料仅供参考,不当之处，请联系改正。表观遗传的定义Epigenetics is referred to heritable traits(over rounds of cell division and sometimes transgenerationally)that do not involve changes to the underlying DNA sequence.在序列没有改变的情况下，基因的功能生了可遗传的变化，并最终导致了表型的变化。这一术语最早是 C.H.Waddi
3、ngton 在1939 首次提出的。Rubin Holiday在1975 进一步完善了表观遗传的内容。1996年,Herman JG 和Baylin SB首次检测到了抑癌基因启动子被甲基化。标志着表观遗传从描述进入了实验，从宏观进入了分子时代。资料仅供参考,不当之处，请联系改正。表观遗传的形式：1.DNA 甲基化（methylation)2.组蛋白的修饰(Histone modifications)，最常见的修饰是乙酰化，甲基化，磷酸化。Histone code3.非编码RNAs。目前研究最多是microRNA,long non-coding RNA,circular RNA4.Prions
4、Note:DNA 甲基化和组蛋白修饰是可逆的，与上面相对应的逆过程分别是：去甲基化，去乙酰话，去磷酸化。资料仅供参考,不当之处，请联系改正。表观遗传的主要研究内容1.DNA 甲基化对基因表达的影响（正常发育和病变）2.组蛋白的修饰对基因表达的影响3.X染色体的失活4.基因印记（gene imprinting)5.细胞的重编程多能干细胞的诱导和分化资料仅供参考,不当之处，请联系改正。获得性可以遗传拉马克与达尔文之争拉马克学说：用进废退和获得性可遗传。例如：长颈鹿的脖子长是因为祖祖辈辈伸长脖子够树叶吃导致的。该学说暗示了表观遗传对性状的决定作用达尔文学说：自然选择，适者生存。长颈鹿的脖子长是因为短
5、脖子的都饿死了。该学说暗示了基因决定性状。资料仅供参考,不当之处，请联系改正。现代遗传学孟德尔中心法则DNA 是遗传物质基因是遗传的基本单位基因决定形状摩尔根的果蝇孟德尔的豌豆资料仅供参考,不当之处，请联系改正。达尔文完胜拉马克现代遗传学的建立奠定了达尔文的现代生物学之父的地位.获得性可遗传的假说被送进了“shadow”（在前苏联例外）为什么表观遗传现在受到如此地关注了呢？表观遗传扩大化的后果：李森科资料仅供参考,不当之处，请联系改正。Genetic tags are passed down through generationsWhen the zygote is formed many e
6、pigenetic tags are removed from the chromosomes of the parents,but some remain 获得性可以遗传资料仅供参考,不当之处，请联系改正。Studies in the field of epigenetics shows that parents experiences are passed on to offspring through epigenetic tagsCell Metab.2016 Feb 16.Paternal Psychological Stress Reprograms Hepatic Glucone
7、ogenesis in Offspring.资料仅供参考,不当之处，请联系改正。The nutrition of the mother can affect the epigenome of a fetus Stress hormones also travel from the mother to a fetus to affect the epigenomeStress,social interactions,physical activity,exposure to toxins and diet are major factors that affect the epigenome 胎
8、教的理论依据资料仅供参考,不当之处，请联系改正。人类基因组计划（）结果是充满了惊奇和困惑：只有大约2,2000基因（在变化中）,编码区域仅占整个基因组的2%。那98%（主要是高度重复序列和一些非编码）的作用是什么？2,2000个基因(和老鼠的基因数量差不多）却能编码一个人？这是一项宏伟的计划，对生物学的研究具有划时代的意义。也充满了期待，认为将对很多人类疾病做出最终的解释和提供治疗线索。资料仅供参考,不当之处，请联系改正。近年来，各大疾病例如癌症，糖尿病等都成上升趋势，为什么？营养（地沟油，三聚氰胺，各种添加剂，化肥农药的不当等），环境污染等外界因素新老问题的困惑老问题新问题易感人群：家族性遗
9、传缺陷携带者患病的几率不同，病征也有所不同染色体的失活一些综合症在DNA 序列上找不到证据和解释同卵双胞胎的表型差异资料仅供参考,不当之处，请联系改正。Identical twins are from the same zygote,so they begin life with the same genetic information,including epigenetic tagsWhile infants they experience the same or very similar environments,so there is little variation in the e
10、pigenomeOver time the twins environments will diverge,resulting in individual epigenetic tags to form for each twin资料仅供参考,不当之处，请联系改正。The difference in the twins epigenomes is what makes them become different when they are olderThe epigenetic tags can have such an effect on the twins that one can dev
11、elop a disease while the other is fineWhen this situation occurs,researchers will try to pinpoint the environmental factors that are responsible for the disease资料仅供参考,不当之处，请联系改正。Pubmed search for epigenetics papers1964-2011 共发表文章 6500多 篇1964-20018653659522002-20062007-20131966-2013 发表的综述2338篇1966-20
12、012002-20062007-493361942资料仅供参考,不当之处，请联系改正。-恶性肿瘤发生发展的表观遗传机制，2011-肺癌发生发展的表观遗传机制，2011-前列腺癌的发生发展的表观遗传机制，2012-若干项关于细胞重新编程和多能干细胞诱导的项目N多个国家科委国家科委973973重大研究计划重大研究计划：国家自然基金委-2011 年141 项-2010年109项-2009年101项批准的关于表观遗传的研究的申请资料仅供参考,不当之处，请联系改正。1.近年，对于表观遗传的研究成爆炸式上升2.国家也投入了很多经费资助表观遗传的研究3.表观遗传对很多种常见疾病的发生具有重要作用Epipro
13、fessors表观遗传热已经蔚然成风！资料仅供参考,不当之处，请联系改正。Type 2 diabetes across generations:from pathophysiology to prevention and management.Lancet.2011 Jul9;378(9786):169-81.Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases.Best Pract Res Clin Gastroenterol.2011 Apr;25(2):269-80.Epigeneti
14、c deregulation in rheumatoid arthritis.Adv Exp Med Biol.2011;711:137-49.A new epigenetic challenge:systemic lupus erythematosus.Adv Exp Med Biol.2011;711:117-36.Does genomic imprinting play a role in autoimmunity?Adv Exp Med Biol.2011;711:103-16.Epigenetic codes of PPAR in metabolic disease.FEBS Let
15、t.2011 Jul 7;585(13):2121-8.Cancer epigenetics and targeted therapies.Oncology(Williston Park).2011 Mar;25(3):228,231.Epigenetics,spermatogenesis and male infertility.Mutat Res.2011 May-Jun;727(3):62-71.表观遗传与疾病：糖尿病，肝病，风湿病，红斑狼疮，代谢病，自身免疫病，肿瘤，男性不育，过敏，创伤后应激，孤独症，心血管疾病孤独症，心血管疾病资料仅供参考,不当之处，请联系改正。.The role
16、of epigenetics in the developmental origins of allergic disease.Ann Allergy Asthma Immunol.2011 May;106(5):355-61;10.Epigenetic aspects of posttraumatic stress disorder.Dis Markers.2011 Jan;30(2-3):77-87.11.Genetic basis of autism:is there a way forward?Curr Opin Psychiatry.2011 May;24(3):226-36.12.
17、Epigenetics in cardiovascular disease.Curr Opin Cardiol.2011 May;26(3):209-15.表观遗传与疾病资料仅供参考,不当之处，请联系改正。外界因子通过表观遗传对基因的表达调控来改变表型资料仅供参考,不当之处，请联系改正。DNA 甲基化对基因的表达调控CpG Island 甲基化状态决定了基因的表达水平甲基基团资料仅供参考,不当之处，请联系改正。甲基化酶DNMT1:维持甲基化的状态DNMT2,3:初始甲基化一个代表：E-cadherin低水平表达E-cadherin是上皮细胞来源的肿瘤恶化的一个标志启动子的CpG island
18、甲基化是调控该基因表达的主要因素。MCF7 MDA-231Sodium bisulfite converts unmethylated cytosines of CpG dinucleotides to uracil or UpG资料仅供参考,不当之处，请联系改正。组蛋白修饰和组蛋白密码(histone code)乙酰化：histone acetyltransferases(HATs)Human proteins that possess HAT catalytic activity include:CREBBP,CDY1,CDY2,CDYL1,CLOCKELP3,EP300HAT1KAT2A
19、,KAT2B,KAT5MYST1,MYST2,MYST3,MYST4NCOA1,NCOA3,NCOATTF3C4甲基化：甲基化转移酶MLL,EZH2,PRMTs磷酸化：磷酸化激酶Aurora,Snlf,ATM/ATR修饰的总和就组成了组蛋白密码资料仅供参考,不当之处，请联系改正。染色体的失活1.哺乳动物的雌性个体中一条染色体失活，并永久保持失活状态。2.大多数动物失活是随机的，在有袋类动物只有父源的染色体失活。3.体细胞的失活发生在胚胎发生的早期。Tortoiseshell cat资料仅供参考,不当之处，请联系改正。Barbara Migeon,Henry Stewart Talks资料仅供参
20、考,不当之处，请联系改正。An example:tortoiseshell cat控制毛色的基因位于X染色体，2个等位基因：橙色（O），黑色（o)。当基因型为杂合体时，X染色体随机失活资料仅供参考,不当之处，请联系改正。染色体具有一个染色体失活中心（），含有个非编码基因(转录产物是non-coding RNAs),Xist,Tsix,Jpx and Ftx.这个non-coding RNAs负责组装失活复合体。该复合体能特意结合失活的染色体，招募PRC2 和YY1 蛋白，并甲基化其和组蛋白，导致该染色体失活。X 染色体的失活机制资料仅供参考,不当之处，请联系改正。Barbara Migeon,
21、Henry Stewart TalksPRC2/YY1，DNMTs资料仅供参考,不当之处，请联系改正。Xist的作用机理资料仅供参考,不当之处，请联系改正。Adrien Bird,Henry Stewart Talks资料仅供参考,不当之处，请联系改正。非编码非编码RNAs 包括tRNA，rRNA,microRNAs,siRNAs,和 the long ncRNAs.Craig MelloRNAi 静默基因表达Andrew Fire2006 诺贝尔生理医学奖资料仅供参考,不当之处，请联系改正。细胞重编程多能干细胞的诱导（iPS cells)干细胞的美好的应用前景和干细胞的数量少促使研究者寻找能
22、够产生大量干细胞的方法。体细胞数量多，但是终极分化的细胞，不具有多能性。Dolly(1996-2003)里程碑1.July 5,1996:Dolly的降生证明了成熟的体细胞具有全能性。2.2006:Yamanaka的小组成功地把小鼠 成纤维细胞诱导成胚胎干细胞特征的细胞，但不能形成chimera.Oct-3/4,SOX2,c-Myc,and Klf43.2007:Yamanaka,和另外个小组独立地在小鼠中诱导了能形成chimera 的胚胎干细胞。4.2007:Thompson 和Yamanaka小组独立地把人的成纤维细胞诱导成了多能干细胞5.2009:周琪和曾凡一联合成功的利用iPS技术培育
23、出了小鼠资料仅供参考,不当之处，请联系改正。1996-2003 Dolly的诞生资料仅供参考,不当之处，请联系改正。2012 Nobel Price WinnerYamanaka,S.(2006).Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors.Cell 126(4):663.Yamanaka,S.(2007).Induction of Pluripotent Stem Cells from Adult Human Fibrobla
24、sts by Defined Factors.Cell 131(5):861872.资料仅供参考,不当之处，请联系改正。细胞重编程上皮间质细胞的转换(EMT)EMT is hot!资料仅供参考,不当之处，请联系改正。1.EMT 的发生是一个渐进的，短暂的，可逆的过程（MET）2.上皮细胞：失去了细胞间的联合结构，细胞的极性，和上皮细胞的标志分子 间质细胞：高表达间质细胞标志分子，细胞的迁移能力和浸润性增加，同时也获得了抗凋亡能力和干细胞的特征。Kalluri R,Weinberg RA.JCI.2009;119(6):1420-8资料仅供参考,不当之处，请联系改正。1.的癌症致死是由于癌转移导
25、致的。控制癌转移是降低癌症患者死亡的关键2.EMT对肿瘤转移的起始至关重要，能赋予上皮细胞来源的肿瘤细胞侵袭和迁移的能力,因而能促进肿瘤转移。因此研究EMT的发生机制将为彻底了解并最终解决肿瘤的转移问题开启了一扇窗户，通过干预或抑制EMT得发生可能是一条新的肿瘤治疗的策略。3.EMT 是干细胞的一个重要来源。研究发现上皮细胞发生EMT的同时，也获得了干细胞的特征。EMT为什么会这么火？资料仅供参考,不当之处，请联系改正。在胚胎发育过程中EMT转换是形成原肠胚（gastrulation）和神经管嵴（neural crest）所必需的。其次，EMT也参与调节多种具有管腔的组织和器官的形成 例如胎盘
26、（placenta）、前体节（somites）、心脏瓣膜（heart valves）、泌尿生殖系统（urogenital tract）、继发腭（secondary palate）等。EMT在伤口愈合、组织重建、器官纤维化等过程中也具有重要作用。资料仅供参考,不当之处，请联系改正。EMT的现象和概念是40多年前由Elizabeth Hay 首先在鸡的早期胚胎发育过程中观察到并提出的。开创了ECM的研究领域第一位发育生物学会的女理事长（1973）Harvard University的第一位女正教授和系主任基础研究系细胞生物学和解剖学（1975）第一位女理事长-细胞生物学会（1976）。美国科学院院
27、士1927-2007资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。剧烈的形态变化基因表达细胞构架的转换：cytokeratin-vimentin胞间联合等结构消失细胞分泌纤维连接蛋白fibronectin细胞获得了抗凋亡的能力细胞的增长受到了抑制细胞获得了干细胞的一些特征资料仅供参考,不当之处，请联系改正。Proteins that increase in abundanceN-cadherinVimentinFibronectinSnail1(Snail)Snail2(Slug)TwistGoosecoidFOXC2Sox10MMP-2MMP-3MMP9Integr
28、in v6Proteins that decrease in abundanceE-cadherenDesmoplakinCytokeratinOccludinProteins that accumulate in the nucleus-cateninSmad-2/3NF-Snail1(Snail)Snail2(Slug)Twist资料仅供参考,不当之处，请联系改正。生长因子：TGFbeta,EGF,FGF,BMP,HGF,PDGF,Wnt,等激素：estrogen Hypoxia转录因子:Snail,Slug,Twist,Zeb1/2,Foxc2,Goosecoid蛋白酶:GSK3 bet
29、a,tyrosine receptor kinases,MMPs MicroRNA:miRNA-10,miRNA-21Notably,mi-RNA200 family are strong inhibitors of EMT资料仅供参考,不当之处，请联系改正。Tumor metastasis-EMT and MET资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。Genetic deletion of the snail gene in mice causes embryonic lethality due to defects in
30、gastrulation and in EMT required for generation of the mesodermal layer.Ectopic expression of Snail in various types of the epithelial cells induces EMT accompanied by increased migration,motility and invasiveness,and also results in the cells to acquire properties of stem cells.Snail is a strong re
31、pressor of E-cadherin.Down-regulation of E-cadherin is a hallmark of EMT and tumor metastasis资料仅供参考,不当之处，请联系改正。Snail or SlugFGFNeural crestGastrulationLimb devptTumor metastasisWntNeural crestHeart devptTumor metastasisTGFSkinPalate fusionTissue fibrosisHeart devptTumor metastasisBMPNeural crestL/R
32、asymmetryMammary devptgastrulationTumor metastasisEGFGSK3-mediatedphosphorylationMTA3EstrogensEMTMetastasisSnail is at the central hub of multiple EMT inducers资料仅供参考,不当之处，请联系改正。X2-Cys-X2-4-Cys-X12-16-His-X3-5-HisThe Cys2His2 zinc finger motif consists an helix and an antiparallel sheet.The zinc ion(
33、green)is coordinated by two histidine residues and two cysteine residues.The Zinc finger binds to the major groove of the DNA duplex.And the binding specificity is determined by the residues located in the helix.The C2H2 zinc finger proteins are the largest family of regulatory proteins in mammals,w
34、hich are encoded by over 700 genes in human genome and approximately comprise 1%of the total proteinsMost members are DNA binding proteins and function as transcriptional regulators.资料仅供参考,不当之处，请联系改正。60SNAG:Snail/Slug,Gfi1资料仅供参考,不当之处，请联系改正。Standing question:the molecular mechanism of SNAG-mediated r
35、epression is unknown.Hypothesis:the SNAG domain may recruit co-factors to mediate its repression functionThe strategy is to perform yeast two-hybrid assays using the SNAG motif as bait to screen a mouse cDNA library and to find potential SNAG binding proteinsE-boxZnZnZnZnZnZnZnZnZnSNAGSnailE-cadheri
36、n Snail target genes资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。Ajuba contains three tandem LIM motifs in the C-terminus and a glycine-proline rich PreLIM in the N-terminus资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。vectorSnailWestern blot资料仅供参考,不当之处，请联系改正。Developmental cell,2008资料仅供参考,不当之处，请联系改正。E-boxZnZnZnZnZnZnZ
37、nZnZnSNAGAjubaLIMSnailpreLIME-cadherin Snail target genesEffectors need to be identifiedHowever,Ajuba itself does not contain any apparent enzymatic activity.It likely functions as a co-regulator by recruiting other chromatin remodeling factors.资料仅供参考,不当之处，请联系改正。Purify Ajuba-associated protein compl
38、exes by large scale affinity chromatography combined with Mass spectrometry(MS):stably express Flag-epitope tagged Ajuba in 293 cells,and the Ajuba associated protein complexes were immunoprecipitated with anti-Flag M2 beads.The components of the complexes were identified by MS.资料仅供参考,不当之处，请联系改正。资料仅
39、供参考,不当之处，请联系改正。Type I:Prmt1,2,3,4,and 6Type II:Prmt5资料仅供参考,不当之处，请联系改正。E-boxZnZnZnZnZnZnZnZnZnSNAGAjubaLIMSnailpreLIMPRMT5MEP50E-cadherin Snail target genesConclusion:Prmt5 is an effector recruited to Snail via an interaction with Ajuba资料仅供参考,不当之处，请联系改正。最近发现14-3-3能阅读组蛋白修饰密码 资料仅供参考,不当之处，请联系改正。资料仅供参考,不
40、当之处，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。Snail recruits Ajuba as a corepressor via its SNAG motif.Ajuba further recruits Prmt5 which confers the Snail complex the transcriptional repression activity by methylate histones14-3-3 binds Ajuba and Snail,which is e
41、ssential for the Snail complex to bind the target chromatin.资料仅供参考,不当之处，请联系改正。PRC2Suz12/Ezh2H3K27me2/3mSin3HDAC1/2Deacetylation LSD1G9aSuv39H1DemethylationH3K9me2AjubaCo-rest资料仅供参考,不当之处，请联系改正。Cancer Research,2014资料仅供参考,不当之处，请联系改正。The Zinc fingers of Snail bind to the RING domain of Ring1B资料仅供参考,不当之处
42、，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。PRC2Suz12/Ezh2H3K27me2/3Ajuba资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。资料仅供参考,不当之处，请联系改正。High levels of Snail,Ring1B and H2AK119Ub1 in PDAC 资料仅供参考,不当之处，请联系改正。H2AK119Ub1 is a biomarker predicting poor prognosis资料仅供参考,不当之处，请联系改正。寻找H2AK119Ub1修饰的染色质位点资料仅供参考,不当之处，请联系改正。Lnc00261 是一个潜在的抑癌基因资料仅供参考,不当之处，请联系改正。
