DNA甲基化功能讲稿.ppt

1 DNA methylation DNA甲基化功能 A few data human genome :about 28 milion CpGs 60–80% are generally methylated. Less than 10% of CpGs occur in CG-dense regions that are termed CpG islands; Half of CGI occur at gene body. A few knowledge 1.Three conserved enzymes DNA methyltransferase 1 (DNMT1): DNA methylation maintenance DNMT3A and DNMT3B:de novo methylation DNMT3L:is a catalytically inactive homologue of DNMT3A and DNMT3B 2.Demethylation:thymidine DNA glycosylase (TDG) ten eleven translocation methylatosine dioxygenase(TET) activation-induced cytodine deaminase(AID) The many roles of DNA methylation DNMT1 DNMT3A/B Cytosine Methyl-cytosine Known features of DNA methylation in mammals unknown features of DNA methylation in mammals FUNCTIONS 转录起始位点的甲基化：有CpG岛的模式，没有CpG岛的模式 Gene body的甲基化 增强子的甲基化 绝缘子的甲基化 Patterns at CpG island transcription start sites 大多数的CGIs保持不甲基化的状态。当在活跃的TSS有CGIs时，他们的启动子区域往往有NDRs（核小体贫乏区域），并且NDRs周围存在核小体变体H2A.Z,和H3K4me3。CGI启动子能够被很多的机制所抑制，比如，myogenic differentiation 1 (MYOD1) or paired box 6 (PAX6)被polycomb蛋白，被抑制的启动子TSS区有核小体以及H3K27me3. 许多被抑制的基因同样存在CGIs的甲基化。这些被甲基化的启动子区域的CGIs大多数都是长时期的稳定的抑制状态。（例如，印记基因） Patterns at non-CpG-island TSSs 1.在TSS区域CpG-poor时，表达的基因往往是未甲基化的，而不表达的基因往往是甲基化的。比如OCT4 and NANOG promoters。 2.但是在05年的全基因组层面上，发现甲基化和表达上没有负相关，但是在08年重分析又发现这个负相关的规律是存在。 3.一个问题是究竟甲基化是表达沉默的原因，还是结果。 Reason or result result：methylation of the Hprt gene on the inactive X chromosome occurred after the chromosome had been inactivated reason：study showed that the methylase was essential for differentiation of a fairly short-lived cell type, it seems possible that DNA methylation has a more instructive role in initiating rather than reinforcing the silencing Genome-wide studies in cancer cells have, however, shown that genes with CGI promoters that are already silenced by Polycomb complexes are much more likely than other genes to become methylated in cancer: that is, the silent state precedes methylation 主流的观点是：DNA甲基化只是起到维持沉默的作用 Gene body methylation 1.在外显子区域的DNA甲基化是C-T突变的重