新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » Nature报道 » Nature:科学家破译“组蛋白密码”识别新机制

Nature:科学家破译“组蛋白密码”识别新机制

来源:中国科学报 2014-03-18 20:02

记者日前从中科院上海应用物理研究所获悉,清华大学医学院基础医学系和结构生物学中心李海涛课题组利用上海光源生物大分子晶体学线站,从结构生物学角度解析组蛋白甲基化修饰识别新机制,进一步揭开了错综复杂的表观遗传调控的神秘面纱。相关成果近期分别在线发表于《自然》和《基因与发育》杂志。

据了解,真核生物基因表达调控不仅依赖于特定的DNA序列元件,还受到特定组蛋白翻译后修饰的精密调节。组蛋白变体和组蛋白修饰赋予组蛋白巨大的信息荷载能力,参与构成一层超越DNA序列的表观遗传信息,在染色质结构调节及基因表达调控等过程中起着关键作用。目前,研究发现很多疾病与组蛋白修饰异常有着非常重要的关联,因此研究组蛋白修饰的产生、消除以及读取机制,对深入了解基因功能调控机制以及疾病的发生和治疗等有着重要意义。

据介绍,此次李海涛课题组利用上海光源生物大分子晶体学线站,解析了bromo-PWWP-H3.1K36me3复合物和bromo-PWWP-H3.3K36me3复合物的晶体结构,并结合从北京光源获得的free bromo-PWWP晶体结构数据,在原子水平上精细阐释了一种肿瘤抑制因子ZMYND11利用其串联“Bromo-ZnF-PWWP”结构域识别组蛋白变体H3.3K36me3修饰的分子机制。进一步研究表明,ZMYND11通过识别组蛋白H3.3K36me3修饰,在转录延伸水平抑制了肿瘤发生相关基因的过度表达,进而抑制肿瘤发生。

该研究首次揭示了生物体内存在组蛋白变体特异的甲基化识别蛋白。这种对组蛋白变体和甲基化修饰类型的双重识别,是组蛋白修饰识别机制上的新亮点,体现了真核生物表观遗传调控的复杂性和重要性。(生物谷Bioon.com)

生物谷推荐的英文摘要

Nature                doi:10.1038/nature13045

ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression

Hong Wen,  Yuanyuan Li,  Yuanxin Xi,  Shiming Jiang,  Sabrina Stratton,  Danni Peng,  Kaori Tanaka,  Yongfeng Ren,  Zheng Xia,  Jun Wu,  Bing Li,  Michelle C. Barton,  Wei Li,  Haitao Li  & Xiaobing Shi

Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription2. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies3. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ‘Ser?31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库