组蛋白H3K56单甲基化修饰的动态调节及其对靶基因转录活性的影响

项目名称： 组蛋白H3K56单甲基化修饰的动态调节及其对靶基因转录活性的影响

项目编号： No.31471209

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 梅品超

作者单位： 中国医学科学院基础医学研究所

项目金额： 90万元

中文摘要： 组蛋白甲基化修饰可以通过影响染色质的高级结构，在基因转录、DNA复制和干细胞分化等诸多方面发挥至关重要的作用。位于核小体entry-exit处的H3K56位点在基因转录调控中可能发挥重要作用，但是该位点的单甲基化修饰H3K56me1研究还有很多未知之处。在前期研究中，我们制备了识别H3K56me1修饰的多克隆抗体并找到了能够特异性去除H3K56单甲基化修饰的组蛋白去甲基化酶KDM56，而且通过ChIP-seq获得了H3K56me1在小鼠干细胞基因组上的分布概貌，本课题将此基础上深入研究KDM56的组蛋白H3K56me1去甲基化酶功能，确定组蛋白H3K56me1的靶基因位点并探究KDM56调控组蛋白H3K56甲基化修饰的分子机制，以及在此过程中组蛋白H3K56me1位点与其他修饰位点之间的互作关系，阐释组蛋白H3K56me1在干细胞自我更新/分化过程中的功能意义。

中文关键词： 组蛋白甲基化；转录调控；染色质修饰；表观遗传学

英文摘要： Histone methylation plays pivotal roles in a variety of DNA-based processes including transcriptional regulation, DNA replication, and stem cell differentation by influencing the structural dynamics of chromatin. Residing at the entry-exit site of double-stranded DNA wrapping around nucleosome, H3K56 might be critical to the transcriptional regulation. However, how the methylation state of H3K56 is regulated and its corresponding epigenetic implication and biological function remain elusive. In our preliminary work, we've identified the demethylase KDM56 that selectively removes mono-methyl mark from H3K56, and got the antibody that can specifically recogonize the H3K56me1 modification. Additionally, the distribution profile of H3K56me1 has been described in mouse stem cell by ChIP-seq analysis. Utilizing a combination of biochemical, molecular biological and epigenetic approaches, we aim to further validate the biochemical characteristics of KDM56, uncover the molecular mechanisms underlying dynamic regulation of H3K56 monomethylation and its effect on the transcriptional activity of target genes and chromatin structure. Moreover, we will also investigate the crosstalk between H3K56me1 and other well-defined histone modifications, and finally reveal the biologial function of H3K56me1 in stem cell self-renewal and differentiation.

英文关键词： Histone-Methylation;Transcriptional-Regulation;Chromatin-Modification;Epigenetics