表观遗传与疾病的课件

,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,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,什么是表观遗传？,1,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,小结表观遗传的主要形式是：DNA methylation,2,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.Waddington,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。,表观遗传的定义Epigenetics is referred,3,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 code,3.,非编码,RNAs,。目前研究最多是,microRNA,long non-coding RNA,circular RNA,4.Prions,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。,表观遗传的形式：1.DNA 甲基化（methylation,4,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,表观遗传的主要研究内容1.DNA 甲基化对基因表达的影响,5,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脖子的都饿死了。该学说暗示了基因决定性状。,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,6,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,现代遗传学孟德尔中心法则DNA 是遗传物质摩尔根的果蝇孟德尔,7,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,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,8,Genetic tags are passed down through generations,When the zygote is formed many epigenetic tags are removed from the chromosomes of the parents,but some remain,获得性可以遗传,Genetic tags are passed down t,9,Studies in the field of epigenetics shows that parents experiences are passed on to offspring through epigenetic tags,Cell Metab.,2016 Feb 16.,Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring.,Studies in the field of epigen,10,Environmental Factors,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 epigenome,Stress,social interactions,physical activity,exposure to toxins and diet are major factors that affect the epigenome,胎教的理论依据,Environmental FactorsThe nutri,11,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。,人类基因组计划（）结果是充满了惊奇和困惑：,12,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,近年来，各大疾病例如癌症，糖尿病等都成上升趋势，为什么？新老,13,Identical Twins,are different,Identical twins are from the same zygote,so they begin life with the same genetic information,including epigenetic tags,While infants they experience the same or very similar environments,so there is little variation in the epigenome,Over time the twins environments will diverge,resulting in individual epigenetic tags to form for each twin,Identical Twins are differentI,14,The difference in the twins epigenomes is what makes them become different when they are older,The epigenetic tags can have such an effect on the twins that one can develop a disease while the other is fine,When this situation occurs,researchers will try to pinpoint the environmental factors that are responsible for the disease,The difference in the twins,15,Pubmed search for epigenetics papers,1964-2011,共发表文章,6500,多 篇,1964-2001,86,536,5952,2002-2006,2007-,2013,1966-201,3,发表的综述,2338,篇,1966-2001,2002-2006,2007-,49,336,1942,Pubmed search for epigenetics,16,-,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,973,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,-恶性肿瘤发生发展的表观遗传机制，2011国家科委973重大,17,1.,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,Epiprofessors,表观遗传热已经蔚然成风！,1.近年，对于表观遗传的研究成爆炸式上升Epiprofe,18,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.,Epigenetic 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 Lett.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,Type 2 diabetes across generat,19,.,The role 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.Epigenetics in,cardiovascular disease,.Curr Opin Cardiol.2011 May;26(3):209-15.,表观遗传与疾病,.The role of epigenetics in,20,外界因子通过表观遗传对基因的表达调控来改变表型,外界因子通过表观遗传对基因的表达调控来改变表型,21,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,DNA 甲基化对基因的表达调控CpG Island 甲基化状,22,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,甲基化,是调控该基因表达的主要因素。,MCF7 MDA-231,Sodium bisulfite converts,un,methylated cytosines of CpG dinucleotides to uracil or UpG,甲基化酶DNMT1:维持甲基化的状态一个代表：E-c,23,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,CLOCK,ELP3,EP300,HAT1,KAT2A,KAT2B,KAT5,MYST1,MYST2,MYST3,MYST4,NCOA1,NCOA3,NCOAT,TF3C4,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,组蛋白修饰和组蛋白密码(histone code)乙酰化：h,24,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,染色体的失活1.哺乳动物的雌性个体中一条染色体失活，,25,Only one X is active,Barbara Migeon,Henry Stewart Talks,Only one X is activeBarbara Mi,26,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,An example:tortoiseshell cat控,27,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,染色体具有一个染色体失活中心（），含有个非编码基,28,Xist Works in Cis,Barbara Migeon,Henry Stewart Talks,PRC2/YY1,，,DNMTs,Xist Works in CisBarbara Migeo,29,Xist,的作用机理,Xist的作用机理,30,Adrien Bird,Henry Stewart Talks,Adrien Bird,Henry Stewart Tal,31,非编码,非编码,RNAs,包括,tRNA,，,rRNA,microRNAs,siRNAs,和,the long ncRNAs.,Craig Mello,RNAi,静默基因表达,Andrew Fire,2006,诺贝尔生理医学奖,非编码非编码RNAs 包括tRNA，rRNA,mic,32,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,Klf4,3.2007: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,技术培育出了小鼠,细胞重编程多能干细胞的诱导（iPS cells)干细胞的,33,1996-2003,Dolly,的诞生,1996-2003 Dolly的诞生,34,2012,Nobel,Price Winner,Yamanaka,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 Fibroblasts by Defined Factors.,Cell,131,(5):861872.,2012 Nobel Price WinnerYamanak,35,细胞重编程上皮间质细胞的转换,(EMT),EMT is hot!,细胞重编程上皮间质细胞的转换(EMT)EMT is h,36,定义：,EMT,是上皮细胞通过基因的重编程而脱分化变成间质细胞的生物学过程,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,定义：EMT 是上皮细胞通过基因的重编程而脱分化变成间质细胞,37,1.,的癌症致死是由于,癌转移,导致的。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？,1.的癌症致死是由于癌转移导致的。控制癌转移是降低,38,EMT,在是胚胎发育过程中的关键事件,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（,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。,EMT在是胚胎发育过程中的关键事件在胚胎发育过程中EMT转换,39,上皮,-,间质细胞转换发现,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,）。,美国科学院院士,1927-2007,上皮-间质细胞转换发现EMT的现象和概念是40多年前由Eli,40,Three subtypes of EMT,Three subtypes of EMT,41,在,EMT,过程中细胞发生了什么改变？,8,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,在EMT过程中细胞发生了什么改变？8剧烈的形态变化,42,EMT Markers,Proteins that increase in abundance,N-cadherin,Vimentin,Fibronectin,Snail1(Snail),Snail2(Slug),Twist,Goosecoid,FOXC2,Sox10,MMP-2,MMP-3,MMP9,Integrin v6,Proteins that decrease in abundance,E-cadheren,Desmoplakin,Cytokeratin,Occludin,Proteins that accumulate,in the nucleus,-catenin,Smad-2/3,NF-,Snail1(Snail),Snail2(Slug),Twist,EMT MarkersProteins that incre,43,EMT,的诱导因子,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 beta,tyrosine receptor kinases,MMPs,MicroRNA:miRNA-10,miRNA-21,Notably,mi-RNA200 family are strong inhibitors of EMT,EMT的诱导因子生长因子：TGFbeta,EGF,FGF,44,Tumor metastasis-EMT and MET,Tumor metastasis-EMT and MET,45,Regulation of,EMT and,metastasis at Snails pace along the way of Ajuba,-,The past,the current and the future,-,Regulation of EMT and metastas,46,The good,the bad and the ugly,The good,the bad and the ugly,47,Snail,是诱导,EMT,和肿瘤转移的关键因子,Genetic deletion of the,snail,gene in mice causes,embryonic lethality,due to defects in 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 repressor of E-cadherin,.Down-regulation of E-cadherin is a hallmark of EMT and tumor metastasis,Snail 是诱导EMT和肿瘤转移的关键因子Genetic,48,Snail or Slug,FGF,Neural crest,Gastrulation,Limb devpt,Tumor metastasis,Wnt,Neural crest,Heart devpt,Tumor metastasis,TGF,Skin,Palate fusion,Tissue fibrosis,Heart devpt,Tumor metastasis,BMP,Neural crest,L/R asymmetry,Mammary devpt,gastrulation,Tumor metastasis,EGF,GSK3,-mediated,phosphorylation,MTA3,Estrogens,EMT,Metastasis,Snail is at the central hub of multiple EMT inducers,Snail or SlugFGFNeural crestWn,49,Snail is a SNAG domain containing C,2,H,2,zinc finger protein,X,2,-Cys-X,2-4,-Cys-X,12-16,-His-X,3-5,-His,The Cys2His2 zinc finger motif consists an,helix,and an antiparallel,sheet,.The,zinc,ion(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,which are encoded by over 700 genes in human genome and approximately comprise 1%of the total proteins,Most members are DNA binding proteins and function as transcriptional regulators.,Snail is a SNAG domain contain,50,Snail is a SNAG domain containing C,2,H,2,zinc finger protein a transcriptional repressor,60,SNAG,:,Sna,il/Slug,G,fi1,Snail is a SNAG domain contain,51,Standing question,:the molecular mechanism of SNAG-mediated repression is unknown.,Hypothesis,:the SNAG domain may recruit co-factors to mediate its repression function,The 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 proteins,E-box,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,SNAG,Snail,E-cadherin,Snail target genes,Standing question:the molecul,52,The LIM protein Ajuba is a specific SNAG binding protein via,an yeast two-hybrid screening,The LIM protein Ajuba is a spe,53,Ajuba and LimD1 belong to the Zyxin/Ajuba family of LIM domain-containing proteins,Ajuba contains three tandem LIM motifs in the C-terminus and a glycine-proline rich PreLIM in the N-terminus,Ajuba and LimD1 belong to the,54,Ajuba interacts with Snail and represses the Snail-target genes,Ajuba interacts with Snail and,55,Snail induces EMT in human mammary epithelial cell MCF10A cells,vector,Snail,Western blot,Snail induces EMT in human mam,56,Ajuba is required for Snail to induce EMT,Developmental cell,2008,Ajuba is required for Snail to,57,E-box,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,SNAG,Ajuba,LIM,Snail,preLIM,E-cadherin,Snail target genes,Effectors need to be identified,However,Ajuba itself does not contain any apparent enzymatic activity.It likely functions as a co-regulator by recruiting other chromatin remodeling factors.,E-boxZnZnZnZnZnZnZnZnZnSNAGAju,58,The Strategy,Purify Ajuba-associated protein complexes 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.,The Strategy Purify Ajuba-asso,59,Affinity purification of Ajuba-interacting proteins from 293 cells,Affinity purification of Ajuba,60,Prmt5 is a type II Protein Arginine methyltransferase,Type I:Prmt1,2,3,4,and 6,Type II:Prmt5,Prmt5 is a type II Protein Arg,61,E-box,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,Zn,SNAG,Ajuba,LIM,Snail,preLIM,PRMT5,MEP50,E-cadherin,Snail target genes,Conclusion:,Prmt5 is an effector recruited to Snail via an interaction with Ajuba,E-boxZnZnZnZnZnZnZnZnZnSNAGAju,62,Snail contains conserved 14-3-3 binding motifs,最近发现,14-3-3,能阅读组蛋白修饰密码,Snail contains conserved 14-3-,63,Snail selectively interacts with 14-3-3 isoforms,Snail selectively interacts wi,64,Mutation of the 14-3-3 binding sites in Snail,Mutation of the 14-3-3 binding,65,Mutation of the 14-3-3 binding motifs impairs the transcriptional repression activity of Snail,Mutation of the 14-3-3 binding,66,The 14-3-3 binding sites in Snail are essential for induction of EMT in MCF10A cells,The 14-3-3 binding sites in Sn,67,Ajuba is a 14-3-3 interacting protein,Ajuba is a 14-3-3 interacting,68,Summary,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 histones,14-3-3 binds Ajuba and Snail,which is essential for the Snail complex to bind the target chromatin.,SummarySnail recruits Ajuba as,69,PRC2,Suz12/Ezh2,H3K27me2/3,mSin3,HDAC1/2,Deacetylation,LSD1,G9a,Suv39H1,Demethylation,H3K9me2,Ajuba,Co-rest,PRC2Suz12/Ezh2H3K27me2/3mSin3H,70,The carboxyl zinc fingers of Snail recruit ubiquitin E3 ligases Ring1A/B,Cancer Research,2014,The carboxyl zinc fingers of S,71,The Zinc fingers of Snail bind to the RING domain of Ring1B,The Zinc fingers of Snail bind,72,Ring1A/B are essential for Snail-mediated repression and cell migration,Ring1A/B are essential for Sna,73,Snail enhances Ring1A/B binding to its target promoter,Snail enhances Ring1A/B bindin,74,PRC2,Suz12/Ezh2,H3K27me2/3,Ajuba,PRC2Suz12/Ezh2H3K27me2/3Ajuba,75,Ezh2 is required for Snail/Ring1A/B to bind target promoter,Ezh2 is required for Snail/Rin,76,Ezh2 and Ring1A/B form two distinct complexes with Snail,Ezh2 and Ring1A/B form two dis,77,High levels of Snail,Ring1B and H2AK119Ub1 in PDAC,High levels of Snail,Ring1B,78,H2AK119Ub1 is a biomarker predicting poor prognosis,H2AK119Ub1 is a biomarker pred,79,寻找,H2AK119Ub1,修饰的染色质位点,寻找H2AK119Ub1修饰的染色质位点,80,Lnc00261,是一个潜在的抑癌基因,Lnc00261 是一个潜在的抑癌基因,81,表观遗传与疾病的课件,82,