郜刚分子生物学-14-真核基因表达调控-4-组蛋白乙酰化与DNA甲基化对基因转录的调控.pptVIP

8.4蛋白质乙酰化与基因表达 本节重点： 组蛋白乙酰化与基因表达的关系 组蛋白乙酰化与DNA甲基化之间的关系 8.4蛋白质乙酰化对基因表达的影响 一些重要的转录因子或者转录共激活因子或者辅助激活因子本身就是组蛋白乙酰基转移酶 转录因子TFIID的一个亚基：TFII250，乙酰化H3、H4； 核受体共激活因子：ACTR，功能同上； 转录共激活因子p300/CBP，乙酰化H2A、H2B、H3、H4 Abbreviations: CREB：cAMP-responsive element-binding protein, CPB：CREB CBP：CREB-binding protein CRE：cAMP-responsive element SRCAP：SNF2-related CBP activator protein PEPCK：phosphoenolpyruvate carboxykinase CAT：chloramphenicol acetyltransferase PKA：protein kinase A TFIIB：transcription factor B TAF：TATA box-binding factor TBP：TATA box-binding protein 2. 组蛋白的乙酰化及去乙酰化对基因表达的影响 组蛋白乙酰化的状态与基因表达有关。组蛋白N端“尾巴”上赖氨酸残基的乙酰化中和了组蛋白尾巴的正电荷，降低了它与DNA的亲和性，导致核小体构象发生有利于转录调节蛋白与染色质相结合的变化（就是染色质重建），从和提高了基因转录的活性。 相反，组蛋白去乙酰化与基因活性的阻遏有关。 组蛋白乙酰基转移酶和去乙酰化酶只能有选择地影响一部分基因的转录。 定义：局部染色质结构发生的变化，包括ATP供能的核小体组蛋白被重建复合体置换等。 经过染色体重建，改变了核小体的结构，暴露出转录激活蛋白的结合位点和TATA box等RNA聚合酶的结合位点 Figure 1: Histone H3-K9 methylation induces DNA methylation, modification which characterizes DNA in heterochromatin and repressive euchromatin. SUVAR39H is a methyltransferase which specifically methylates the Lysine 9 of histone H3. Such a methylation creates a binding site for the Heterochromatin Protein HP1 which recruits a DNA methyl transferase, capable to methylate the CpG in DNA (Me= Methyl; Methyl H3-K9= Methyl on Lysin 9 of Histone H3; HP1=Heterochromatin Protein 1; DNMT=DNA Methyl transferase). Figure 2: DNA methylation induces Histone de-acetylation, modification which characterizes histones in both heterochromatin and repressed euchromatin. MeCP2 specifically binds to methylated DNA, and recruits an HDAC which de-acetylates histones (Ac= Acetyl; Me= Methyl; MeCP2= Methyl-CpG binding Protein 2; HDAC= Histone De-Acetylase). The mechanism whereby DNA methylation and histone deacetylation cooperate to repress transcription. From the following article:Keith D. Robertson Alan P. Wolffe, Nature Reviews Genetics 1, 11-19 (October 2000) 组蛋白的乙酰化是可逆的 组蛋白去乙酰化酶负责去除组蛋白上的乙酰基团。 去乙酰化：组蛋白去乙酰化酶（HDAC，histone deacetylase） 目前研究比较深入的是