中文摘要：

染色质地貌和细胞代谢对细胞命运决定有着重要的作用,但人们对它们之间的互相作用却了解甚少。我们运用基因组范围的si RNA筛选,发现PHB对于维持人胚胎干细胞的自我更新具有重要的作用。其具体机制如下：PHB可以和H3.3的伴侣蛋白HIRA形成蛋白复合体;与PHB相似的是,HIRA对人胚胎干细胞特性的维持也起着重要的作用;特别是PHB和HIRA对异柠檬酸脱氢酶启动子区域染色质结构的调节,调控着对胚胎干细胞命运有着重要作用的代谢产物—α-酮戊二酸的产生。我们的研究揭示了在人胚胎干细胞的细胞核中,PHB通过与HIRA复合体相互作用参与维持正常染色质的结构和重要代谢产物的生成,进而使人胚胎干细胞处于自我更新状态。

英文摘要：

The chromatin landscape and cellular metabolism both contribute to cell fate determination,but their interplay remains poorly understood.Using genome-wide siR NA screening,we have identified prohibitin（PHB）as an essential factor in self-renewal of human embryonic stem cells（hE SCs）.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 hE SCs self-renewal.PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hE SCs.Of particular note,PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and,thus,production ofα-ketoglutarate,a key metabolite in the regulation of ESC fate.Our study shows that PHB has an unexpected nuclear role in hE SCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit.