PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs
PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs
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PHB 与 HIRA 复合物联合控制人类 ESC 中的表观遗传代谢回路
DOI：
10.1016/j.stem.2016.11.002
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发表时间：
2017-02-02
期刊：
影响因子：
23.9
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Zhu, Zhexin;Li, Chunliang;Jin, Ying
染色质景观和细胞代谢都有助于细胞命运的决定，但他们的相互作用仍然知之甚少。使用全基因组siRNA筛选，我们已经确定了抑制素（PHB）作为人类胚胎干细胞（hESC）自我更新的一个重要因素。在机制上，PHB与HIRA（一种组蛋白H3.3伴侣）形成蛋白复合物，并稳定HIRA复合物组分的蛋白水平。与PHB一样，HIRA也是hESC自我更新所必需的。PHB和HIRA共同控制hESC中组蛋白H3.3的整体沉积和基因表达。特别值得注意的是，PHB和HIRA调节异柠檬酸脱氢酶基因启动子处的染色质结构，以促进转录，从而促进α-酮戊二酸的产生，α-酮戊二酸是调节ESC命运的关键代谢物。我们的研究表明，PHB在hESC中具有意想不到的核作用，这是自我更新所需的，并且它与HIRA在染色质组织中起作用，将表观遗传组织与代谢回路联系起来。
The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of a-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit.