國(guó)際學(xué)術(shù)期刊《基因和發(fā)育》(Genes and Development) 9月12日在線(xiàn)發(fā)表了中科院上海生命科學(xué)研究院生化與細(xì)胞所王綱研究組的最新研究成果,。該工作揭示了中介體復(fù)合物(Mediator Complex)的Med23亞基在脂肪和平滑肌發(fā)育中的“陰陽(yáng)”調(diào)控作用，為脂肪和平滑肌相關(guān)疾病的研究和治療提供了新的理論支持,。
脂肪和平滑肌細(xì)胞同屬于中胚層來(lái)源,，已有的研究證明二者在發(fā)育上存在密切的關(guān)系，它們有可能來(lái)源于相同的祖細(xì)胞,。不過(guò)，這兩種細(xì)胞命運(yùn)是如何調(diào)控的分子機(jī)制仍不清楚,。在王綱研究員指導(dǎo)下,，博士研究生尹景雯等通過(guò)一系列的分子與細(xì)胞生物學(xué)實(shí)驗(yàn)，證明了Mediator復(fù)合物的Med23亞基在脂肪和平滑肌分化過(guò)程中起到“陰陽(yáng)”調(diào)控作用,。該研究發(fā)現(xiàn),，Med23亞基對(duì)于Ras/ELK1和 RhoA/MAL兩條信號(hào)通路具有相反的調(diào)控作用,，Med23亞基的缺失將會(huì)導(dǎo)致Ras/ELK1靶基因的表達(dá)減弱，而RhoA/MAL靶基因表達(dá)增強(qiáng),，而這兩條信號(hào)通路分別對(duì)于脂肪分化和平滑肌分化是必須的,；因此，Med23的表達(dá)水平對(duì)于調(diào)控脂肪和平滑肌的平衡起了至關(guān)重要的作用,。這一現(xiàn)象在斑馬魚(yú)發(fā)育系統(tǒng)中得到了進(jìn)一步的驗(yàn)證,。
哺乳動(dòng)物的中介體復(fù)合物是由30多個(gè)亞基構(gòu)成的龐大復(fù)合物，它作為一個(gè)控制中心,，通過(guò)不同的亞基響應(yīng)不同的通路信號(hào),，控制特定的基因表達(dá)和生物學(xué)過(guò)程。王綱研究組這項(xiàng)關(guān)于Med23最新研究發(fā)現(xiàn),，中介體復(fù)合物亞基能夠正反調(diào)控兩種細(xì)胞命運(yùn),，揭示了細(xì)胞命運(yùn)調(diào)控的新機(jī)制，這一發(fā)現(xiàn)也為治療一系列脂肪和平滑肌相關(guān)疾?。ㄈ绶逝?、糖尿病、動(dòng)脈粥樣硬化,、高血壓等）提供了可能的干預(yù)靶點(diǎn),。
該項(xiàng)工作得到上海生科院健康科學(xué)研究所高平進(jìn)教授、計(jì)算生物學(xué)研究所嚴(yán)軍教授,、南京大學(xué)模式動(dòng)物中心楊中州,、朱敏生教授、美國(guó)新澤西醫(yī)科大學(xué)田斌教授,、上海生命科學(xué)信息中心李黨生教授的大力協(xié)助,，并獲得了中科院、科技部,、國(guó)家自然科學(xué)基金委和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi: 10.1101/gad.192666.112
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Mediator MED23 plays opposing roles in directing smooth muscle cell and adipocyte differentiation
Yin JW, Liang Y, Park JY, Chen D, Yao X, Xiao Q, Liu Z, Jiang B, Fu Y, Bao M, Huang Y, Liu Y, Yan J, Zhu MS, Yang Z, Gao P, Tian B, Li D, Wang G.
The Mediator complex functions as a control center, orchestrating diverse signaling, gene activities, and biological processes. However, how Mediator subunits determine distinct cell fates remains to be fully elucidated. Here, we show that Mediator MED23 controls the cell fate preference that directs differentiation into smooth muscle cells (SMCs) or adipocytes. Med23 deficiency facilitates SMC differentiation but represses adipocyte differentiation from the multipotent mesenchymal stem cells. Gene profiling revealed that the presence or absence of Med23 oppositely regulates two sets of genes: the RhoA/MAL targeted cytoskeleton/SMC genes and the Ras/ELK1 targeted growth/adipogenic genes. Mechanistically, MED23 favors ELK1-SRF binding to SMC gene promoters for repression, whereas the lack of MED23 favors MAL-SRF binding to SMC gene promoters for activation. Remarkably, the effect of MED23 on SMC differentiation can be recapitulated in zebrafish embryogenesis. Collectively, our data demonstrate the dual, opposing roles for MED23 in regulating the cytoskeleton/SMC and growth/adipogenic gene programs, suggesting its "Ying-Yang" function in directing adipogenesis versus SMC differentiation.
