肿瘤的表观遗传调控.pptVIP

肿瘤的表观遗传调控(Epigenetic Regulation of Cancer) Chromatin packaging 表观遗传学概念 表观遗传(epigenetics)的概念是在1942年由Waddington提出。指DNA序列不发生变化但是基因表达却发生了可遗传的改变，也就是说基因型未变化而表型却发生了改变，这种变化是细胞内除了遗传信息以外的其他可遗传物质的改变，并且这种改变在发育和细胞增殖过程中能稳定地传递下去。 Cancer epigenetics In addition to having genetic causes, cancer can also be considered an epigenetic disease. Regulation by genetics involves a change in the DNA sequence, whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region 表观遗传修饰从多个水平调控基因表达 Enzymatic methylation of the C–5 position of cytosine residues can effect epigenetic inheritance by altering the expression of genes and by transmission of DNA methylation patterns through cell division. Thus, in addition to its well–known role in deamination mutational hotspots in human DNA, DNA methylation may contribute to gene inactivation in cancer. 癌细胞的整个基因组水平处于低甲基化状态，比正常低20%～60%，这种低甲基化大多发生于编码区和内含子区域，以及约占人类基因组20%～30%的重复序列区 抑癌基因启动子区域CpG岛高度甲基化，且与DNA结合的组蛋白广泛去乙酰化 Gene silencing DNA methylation is a powerful mechanism for the suppression of gene activity. There is reciprocal relationship between the density of methylated cytosine residues and the transcriptional activity of a gene. The methyl groups do not affect base pairing but can influence protein–DNA interactions by protruding into the major groove. ●The strong effect of 5–methylcytosine (5mC) in mammalian promoter regions suggests that DNA methylation inhibits transcription by interfering with transcription initiation. ● DNA methylation reduces the binding affinity of sequence–specific transcription factors. ● Methylation–dependent, sequence–specific DNA–binding proteins, such as MDBP may act as transcriptional repressors. Histone modifications— including acetylation, methylation and phosphorylation — are important in transcriptional regulation and many are stably maintained during cell division, although the mechanism for this epigenetic inheritance i