BRD4 短亚型在相分离和活性基因转录中的作用。
Roles of the BRD4 short isoform in phase separation and active gene transcription.
机构信息
Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, Jilin, China.
International Center of Future Science, Jilin University, Changchun, China.
出版信息
Nat Struct Mol Biol. 2020 Apr;27(4):333-341. doi: 10.1038/s41594-020-0394-8. Epub 2020 Mar 16.
BRD4, a major tandem-bromodomain-containing transcription regulator, has two isoforms. The long isoform (BRD4L) has an extended C terminus that binds transcription cofactors, while the short isoform (BRD4S) lacks this C-terminal extension. Unlike BRD4L, the role of BRD4S in gene transcription remains unclear. Here, we report that, in human cancer cells, BRD4S forms nuclear puncta that possess liquid-like properties and that colocalize with BRD4L, MED1 and sites of histone H3 lysine 27 acetylation. BRD4 puncta are correlated with BRD4S but not BRD4L expression levels. BRD4S knockdown reduces BRD4S condensation, and ectopic expression promotes puncta formation and target gene transcription. BRD4S nuclear condensation is mediated by its intrinsically disordered regions and binding of its bromodomains to DNA and acetylated chromatin, respectively, and BRD4S phosphorylation diminishes BRD4 condensation. Our study illuminates a previously unappreciated role of BRD4S in organizing chromatin and transcription factors through phase separation to sustain gene transcription in chromatin for cancer cell proliferation.
BRD4 是一种主要的串联溴结构域转录调节剂,有两个亚型。长亚型(BRD4L)具有一个延伸的 C 端,可与转录共因子结合,而短亚型(BRD4S)则缺乏这个 C 端延伸。与 BRD4L 不同,BRD4S 在基因转录中的作用尚不清楚。在这里,我们报告在人类癌细胞中,BRD4S 形成具有液态特性的核斑点,与 BRD4L、MED1 和组蛋白 H3 赖氨酸 27 乙酰化位点共定位。BRD4 斑点与 BRD4S 而不是 BRD4L 的表达水平相关。BRD4S 敲低会减少 BRD4S 的凝聚,而过表达则会促进斑点形成和靶基因转录。BRD4S 核凝聚是由其固有无序区域介导的,其溴结构域分别与 DNA 和乙酰化染色质结合,而 BRD4S 的磷酸化会减少 BRD4 的凝聚。我们的研究揭示了 BRD4S 通过相分离来组织染色质和转录因子的先前未被认识的作用,以维持染色质中的基因转录,从而促进癌细胞增殖。