近日,国际权威期刊Nucleic Acids Research(IF 7.836 2010)上发表了厦门大学生命科学学院研究人员的最新研究成果“Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation。”
厦门大学生命科学学院的陈瑞川教授和刘润忠副教授为这篇文章的共同通讯作者。前者的主要研究方向是P-TEFb活性调控的分子机制研究,以寻找调控其活性的细胞信号途径,及其对HIV复制、心肌肥大和肿瘤细胞生长与分化的影响。后者主要从事神经退行性疾病的病理机制及整形转录延伸因子P-TEFb在神经干细胞中的转录调节作用机理研究。
在这篇文章中,研究人员首次发现静息状态细胞内75%~80%的P-TEFb被束缚于7SK snRNP复合物中,其余部分已经在染色质上,同时,绝大部分Brd4富集在染色质上,但并不用于转录也不与染色质上的P-TEFb结合。借助信号刺激和抑制剂抑制等试验模式, 解释外界信号诱导P-TEFb从无活性复合物释放和诱导Brd4从染色质解离的双重作用,阐释了解离的Brd4介导P-TEFb在启动子区的应激募集,从而刺激应激性基因转录表达的信号和分子机制。
新研究为深入理解细胞生长,分化及应激调控机制提供了全新的思路,而且对细胞应激调控等相关领域的研究也多有助益。此外,由于Brd4所募集的P-TEFb复合体的活性异常与心肌肥大、HIV-1转录活化以及癌症等恶性疾病的病理性病变过程密切相关,因此可能会促进对这些恶性疾病的发病机理的阐释, 为寻找、筛选新的治疗策略和药物靶点及用药禁忌提供必要的理论基础和可靠的实验模型。(生物谷Bioon.com)
doi: 10.1093/nar/gkr698
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Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation
Nanping Ai, Xiangming Hu, Feng Ding, Bingfei Yu, Huiping Wang, Xiaodong Lu, Kai Zhang, Yannan Li, Aidong Han, Wen Lin, Runzhong Liu* and Ruichuan Chen*
Bromodomain-containing protein Brd4 is shown to persistently associate with chromosomes during mitosis for transmitting epigenetic memory across cell divisions. During interphase, Brd4 also plays a key role in regulating the transcription of signal-inducible genes by recruiting positive transcription elongation factor b (P-TEFb) to promoters. How the chromatin-bound Brd4 transits into a transcriptional regulation mode in response to stimulation, however, is largely unknown. Here, by analyzing the dynamics of Brd4 during ultraviolet or hexamethylene bisacetamide treatment, we show that the signal-induced release of chromatin-bound Brd4 is essential for its functional transition. In untreated cells, almost all Brd4 is observed in association with interphase chromatin. Upon treatment, Brd4 is released from chromatin, mostly due to signal-triggered deacetylation of nucleosomal histone H4 at acetylated-lysine 5/8 (H4K5ac/K8ac). Through selective association with the transcriptional active form of P-TEFb that has been liberated from the inactive multi-subunit complex in response to treatment, the released Brd4 mediates the recruitment of this active P-TEFb to promoter, which enhances transcription at the stage of elongation. Thus, through signal-induced release from chromatin and selective association with the active form of P-TEFb, the chromatin-bound Brd4 switches its role to mediate the recruitment of P-TEFb for regulating the transcriptional elongation of signal-inducible genes.