06表观遗传学.ppt

* * * * * * * * * * Epigenetic modifications leading to gene transcriptonal regulation. TF: transcriptional factors; DNMT: DNA methyltransferase; HAT: Histone acetyltransferase; HDAC: Histone deacetylase; MBP: Methyl-CpG binding protein; HMT: Histone methyltransferase. Modifications of the histone H3 tails, Lys4 (K4) and Lys9 (K9), are indicated. Ac: acetylation; Me: methylation * Epigenetic differences arise in MZ twins. (A) Two representative examples of the determination of monozygosity using microsatellite markers. (B) Quantification of X chromosome inactivation by PCR amplification of the androgen receptor locus after digestion with the DNA methylation-sensitive and -insensitive restriction enzymes HpaII and MSp I, respectively. Two examples of a different pattern of X inactivation between MZ twin pairs are shown. (C Upper) Quantification of global 5mC DNA content (Left), histone H4 acetylation (Center), and histone H3 acetylation (Right) by HPLC and high-performance capillary electrophoresis. (C Lower) Comparison of epigenetic values between the siblings of each 3- and 50-year-old twin pair. Results are expressed as mean ± SD. * * Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. Disorder affecting chromatin structure in trans: Caused by mutation in gene encoding proteins essential for chromatin structure and remodeling. Disorder affecting chromatin structure in cis: caused by abnormal change in genomic DNA. DNA水平：DNA共价结合修饰基团，使序列相同的等位基因处于不同修饰状态，例如DNA甲基化 RNA水平：非编码RNA可通过某些机制实现对基因转录以及转录后的调控，例如microRNA、RNA干扰等 蛋白质水平：通过对蛋白质的修饰或改变其构象实现对基因表达的调控，例如组蛋白修饰 染色质水平：通过染色质位置、结构的变化实现对基因表达的调控，例如染色质重塑 以上几个水平之间相互关联，任何一方面的异常都将影响染色质结构和基因表达。 * * * 一般而言，DNA甲基化会抑制基因的表达。发生在基因启动子或其附近区域的甲基化将直接阻碍转录因子与启动子结合，使基因不能转录或降低基因的转录水平。 同时，基因5’端的调控元件发生甲基化后能结合特定甲基化CpG序列结合蛋白（methyl CpG binding protein，MBP），从而间接阻止转录因子与启动子形成转录复合体。 甲基化还能改变染色质的构象，使染色质凝缩成非活性的高级结构。 * * * 基因启动子区的CpG岛在正常状态下一般是非甲基化的