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PLoS Genet:朱冰等揭示组蛋白四聚体拆分研究获进展

来源:NIBS 2013-06-20 00:52

2013年6月6日,北京生命科学研究所朱冰实验室在《PLOS Genetics》杂志上在线发表题为“H3.3-H4 tetramer splitting events feature cell-type specific enhancers”的文章。这篇文章首次报道了组蛋白H3.3-H4四聚体拆分事件的全基因组分布情况,并发现H3.3-H4四聚体拆分事件富集于增强子。

组蛋白修饰是表观遗传信息的重要组成部分,其承载的表观遗传信息在细胞有丝分裂过程中的继承机制是表观遗传领域的重要问题和朱冰实验室的主要研究方向。

组蛋白H3-H4四聚体是核小体的核心组成部分,该四聚体在DNA复制中的分配模式是组蛋白修饰继承性研究的基本问题。朱冰实验室徐墨等人结合定量质谱技术与传统生物化学手段,在数年前澄清了四聚体分配方式这一长期争论的问题(Xu et al., Science. 2010)。该工作发现常规组蛋白四聚体通过全保留方式进行分配,并意外地发现一部分含组蛋白变体H3.3的H3-H4四聚体会发生拆分事件,产生含一分子“新”H3.3和一分子“旧”H3.3的混合型核小体。H3.3-H4四聚体的拆分事件是一个全新的发现,其机理和功能意义均未知。

在本研究中,朱冰实验室建立了一个可经双重诱导表达两种带不同标签组蛋白H3.3的HeLa稳定细胞系,通过控制两种外源H3.3的表达时序并利用双轮亲和纯化获得含一分子“新”H3.3和一分子“旧”H3.3的混合型单核小体,也即发生了拆分事件的H3.3核小体。然后通过DNA高通量测序,首次测定了组蛋白H3.3-H4四聚体拆分事件的全基因组分布谱,并发现H3.3-H4四聚体拆分事件显著富集于增强子。表明该事件可能参与增强子的功能调节。

我所与中国农业大学联合培养的黄畅博士以及朱冰实验室张珠强博士为本论文的共同第一作者,其他作者还有徐墨博士,李颖峰,李珍,马妍婷和蔡涛博士。朱冰博士为本文通讯作者。该研究由科技部、北京市科委和HHMI国际青年科学家项目资助,在北京生命科学研究所完成。(生物谷Bioon.com)

H3.3-H4 Tetramer Splitting Events Feature Cell-Type Specific Enhancers

Huang C, Zhang Z, Xu M, Li Y, Li Z, et al

Previously, we reported that little canonical (H3.1–H4)2 tetramers split to form “hybrid” tetramers consisted of old and new H3.1–H4 dimers, but approximately 10% of (H3.3–H4)2 tetramers split during each cell cycle. In this report, we mapped the H3.3 nucleosome occupancy, the H3.3 nucleosome turnover rate and H3.3 nucleosome splitting events at the genome-wide level. Interestingly, H3.3 nucleosome turnover rate at the transcription starting sites (TSS) of genes with different expression levels display a bimodal distribution rather than a linear correlation towards the transcriptional activity, suggesting genes are either active with high H3.3 nucleosome turnover or inactive with low H3.3 nucleosome turnover. H3.3 nucleosome splitting events are enriched at active genes, which are in fact better markers for active transcription than H3.3 nucleosome occupancy itself. Although both H3.3 nucleosome turnover and splitting events are enriched at active genes, these events only display a moderate positive correlation, suggesting H3.3 nucleosome splitting events are not the mere consequence of H3.3 nucleosome turnover. Surprisingly, H3.3 nucleosomes with high splitting index are remarkably enriched at enhancers in a cell-type specific manner. We propose that the H3.3 nucleosomes at enhancers may be split by an active mechanism to regulate cell-type specific transcription.

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