组蛋白H3
RNA聚合酶Ⅱ
染色质
生物
细胞生物学
组蛋白
抄写(语言学)
染色质免疫沉淀
分子生物学
基因表达
基因
遗传学
发起人
语言学
哲学
作者
Hong Wen,Yuanyuan Li,Yuanxin Xi,Shiming Jiang,Sabrina A. Stratton,Danni Peng,Kaori Tanaka,Yong-Feng Ren,Zheng Xia,Jun Wu,Bing Li,Michelle Barton,Wei Li,Haitao Li,Xiaobing Shi
出处
期刊:Nature
[Springer Nature]
日期:2014-03-02
卷期号:508 (7495): 263-268
被引量:286
摘要
Candidate tumour suppressor ZMYND11 specifically recognizes histone K36 trimethylation on the histone variant H3.3 and helps regulate transcription elongation. This study identifies the PHD–bromo–PWWP cassette of the candidate tumour suppressor ZMYND11 as a specific 'reader' of trimethylated K36 on the histone variant H3.3. ZMYND11 seems to accumulate on gene bodies during transcription and functions in modulating transcription elongation. Structural and genomics experiments reveal the chromatin-binding properties of ZMYND11, and it is shown to be important for repressing transcription of genes linked to tumour cell growth. 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI