近日,，國(guó)際權(quán)威期刊Nucleic Acids Research（IF 7.836 2010）上發(fā)表了廈門(mén)大學(xué)生命科學(xué)學(xué)院研究人員的最新研究成果“Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation。”
廈門(mén)大學(xué)生命科學(xué)學(xué)院的陳瑞川教授和劉潤(rùn)忠副教授為這篇文章的共同通訊作者,。前者的主要研究方向是P-TEFb活性調(diào)控的分子機(jī)制研究,，以尋找調(diào)控其活性的細(xì)胞信號(hào)途徑,，及其對(duì)HIV復(fù)制、心肌肥大和腫瘤細(xì)胞生長(zhǎng)與分化的影響,。后者主要從事神經(jīng)退行性疾病的病理機(jī)制及整形轉(zhuǎn)錄延伸因子P-TEFb在神經(jīng)干細(xì)胞中的轉(zhuǎn)錄調(diào)節(jié)作用機(jī)理研究,。
在這篇文章中，研究人員首次發(fā)現(xiàn)靜息狀態(tài)細(xì)胞內(nèi)75%～80%的P-TEFb被束縛于7SK snRNP復(fù)合物中,，其余部分已經(jīng)在染色質(zhì)上,，同時(shí)，絕大部分Brd4富集在染色質(zhì)上,，但并不用于轉(zhuǎn)錄也不與染色質(zhì)上的P-TEFb結(jié)合,。借助信號(hào)刺激和抑制劑抑制等試驗(yàn)?zāi)Ｊ? 解釋外界信號(hào)誘導(dǎo)P-TEFb從無(wú)活性復(fù)合物釋放和誘導(dǎo)Brd4從染色質(zhì)解離的雙重作用，闡釋了解離的Brd4介導(dǎo)P-TEFb在啟動(dòng)子區(qū)的應(yīng)激募集,，從而刺激應(yīng)激性基因轉(zhuǎn)錄表達(dá)的信號(hào)和分子機(jī)制,。
新研究為深入理解細(xì)胞生長(zhǎng)，分化及應(yīng)激調(diào)控機(jī)制提供了全新的思路,，而且對(duì)細(xì)胞應(yīng)激調(diào)控等相關(guān)領(lǐng)域的研究也多有助益,。此外，由于Brd4所募集的P-TEFb復(fù)合體的活性異常與心肌肥大,、HIV-1轉(zhuǎn)錄活化以及癌癥等惡性疾病的病理性病變過(guò)程密切相關(guān),，因此可能會(huì)促進(jìn)對(duì)這些惡性疾病的發(fā)病機(jī)理的闡釋?zhuān)?為尋找、篩選新的治療策略和藥物靶點(diǎn)及用藥禁忌提供必要的理論基礎(chǔ)和可靠的實(shí)驗(yàn)?zāi)Ｐ?。（生物谷Bioon.com）
doi: 10.1093/nar/gkr698
PMC:
PMID:
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.
