表观遗传学说课

1、表观遗传学说课基因表达模式一个多细胞生物机体的不同类型细胞概 述相同的基因型 不同的表型 基因表达模式在细胞世代之间的可遗传性并不依赖细胞内DNA的序列信息。决定细胞类型的不是基因本身，而是基因表达模式，通过细胞分裂来传递和稳定地维持具有组织和细胞特异性的基因表达模式对于整个机体的结构和功能协调是至关重要的。基因表达模式 (gene expression pattern)基因表达模式的信息标记表观遗传修饰(epigenetic modification)DNA分子的特定碱基的结构修饰 (如胞嘧啶的甲基化)染色质构型重塑(chromatin remodeling) (如组蛋白的构型变化)表观遗传

2、(epigenetic inheritance)：通过有丝分裂或减数分裂来传递非DNA序列信息的现象。表观遗传学(epigenetics)：则是研究不涉及DNA序列改变的基因表达和调控的可遗传变化的。或者说是研究从基因演绎为表型的过程和机制的一门新兴的遗传学分支。表观遗传修饰机制DNA甲基化和染色质重塑基因组印迹基因表达重新编程X染色体失活表观遗传修饰机制 DNA甲基化(DNA methylation)是研究得最清楚、也是最重要的表观遗传修饰形式，主要是基因组DNA上的胞嘧啶第5位碳原子和甲基间的共价结合，胞嘧啶由此被修饰为5甲基胞嘧啶(5-methylcytosine，5-mC)。DNA甲基

3、化（一） DNA甲基化和染色质重塑 DNMT1SAM胞嘧啶5-甲基胞嘧啶胞嘧啶甲基化反应DNA甲基化 DNA复制酶CH3CH3CH3CH3DNA甲基转移酶CH3CH3CH3CH3DNA复制后甲基化型的维持DNA甲基化结构基因5端附近富含CpG二联核苷的区域称为CpG岛(CpG islands)。 DNA甲基化哺乳动物基因组DNA中5-mC约占胞嘧啶总量的2%-7%，绝大多数5-mC存在于CpG二联核苷(CpG doublets)。基因调控组件(如启动子)所含CpG岛中的5-mC会阻碍转录因子复合体与DNA的结合，所以DNA甲基化一般与基因沉默(gene silence)相关联；而非甲基化(no

4、n -methylated)一般与基因的活化(gene activation)相关联。而去甲基化(demethylation)往往与一个沉默基因的重新激活(reactivation)相关联。DNA甲基化Model for methylation-dependent gene silencing. The structural element of chromatin is the nucleosomal core, which consists of a 146-bp DNA sequence wrapped around core histones. Acetylation of the h

5、istones causes an open chromatin config-uration that is associated with transcriptional activity. Methylated cytosines are recognized by methyl-CpG-binding proteins (MBDs), which in turn recruit histone deacetylases (HDACs) to the site of methylation, convert-ing the chromatin into a closed structur

6、e that can no longer be accessed by the transcriptional machinery.组成核小体的组蛋白可以被多种化学加合物所修饰，如磷酸化、乙酰化和甲基化等，组蛋白的这类结构修饰可使染色质的构型发生改变，称为染色质构型重塑。组蛋白中不同氨基酸残基的乙酰化一般与活化的染色质构型常染色质(euchromatin)和有表达活性的基因相关联；而组蛋白的甲基化则与浓缩的异染色质(hetero -chromatin)和表达受抑的基因相关联。染色质重塑 Epigenetics is an advanced biological system that sele

7、ctively utilizes genomic information and is involved in various fundamental phenomena. Specifically, it puts emphasis on the regulation of gene expression, through DNA methylation, chromatin, and post-translational modification of proteins such as histones. Arrows indicate possible functional intera

8、ctions between them. DNA hypermethylation, histone hypoacetylation and inactive chromatin repress transcription. In contrast, a transcriptionally active condition may encourage DNA hypomethylation, histone hyperacetylation and active chromatin. Also, a particular chromatin structure may be required for establishing