干细胞和细胞重编程代谢至关重要的miRNA

　　

　近日，中国科学技术大学高平课题组和北京大学汪阳明课题组合作研究，发现了miRNA对于维持干细胞糖代谢水平和调控体细胞重编程中代谢转换至关重要。研究成果发表在EMBO Journal上。中国科大博士生曹洋和北京大学博士生郭文婷为共同第一作者。

　　近年来的研究发现，胚胎干细胞和诱导多能性干细胞的代谢方式也存在有氧糖酵解增强的现象，即类似于肿瘤细胞中的Warburg effect，但其背后的调控机制及其对干细胞多能性的影响并不清楚。

   为了探究这一科学问题，研究人员采用Dgcr8-/-干细胞体系研究miRNA对代谢的调控作用，发现将miRNA加工蛋白Dgcr8敲除后，干细胞中的葡萄糖摄取、乳酸产生等指标明显降低，说明细胞糖代谢水平受到明显削弱。将miR-290 簇miRNA回补后将逆转这一现象。

   机制研究发现miR-290簇通过靶向抑制DNA甲基结合蛋白Mbd2，从而解除Mbd2对癌基因Myc的抑制。活化的Myc作为转录因子促进糖代谢酶Pkm2和Ldha的表达，进而促进干细胞代谢水平和体细胞重编程。这一通路在人的细胞中也保守存在（人的细胞中同源是miR-371簇）。miR-290-Mbd2-Myc-Pkm2/Ldha这一调控通路的发现揭示了miRNA调控干细胞代谢和体细胞重编程的新机制。

    上述研究工作得到了科技部、国家自然科学基金委和中科院等的资助。

研究揭示miRNA调控干细胞代谢新机制

原文摘要：

miR‐290/371‐Mbd2‐Myc circuit regulates glycolytic metabolism to promote pluripotency

Enhanced glycolysis is a main feature of pluripotent stem cells (PSCs) and is proposed to be important for the maintenance and induction of pluripotency. The molecular mechanism underlying enhanced glycolysis in PSCs is not clear. Using Dgcr8−/− mouse embryonic stem cells (ESCs) that lack mature miRNAs, we found that miR‐290 cluster of miRNAs stimulates glycolysis by upregulating glycolytic enzymes Pkm2 and Ldha, which are also essential for the induction of pluripotency during reprogramming. Mechanistically, we identified Mbd2, a reader for methylated CpGs, as the target of miR‐290 cluster that represses glycolysis and reprogramming. Furthermore, we discovered Myc as a key target of Mbd2 that controls metabolic switch in ESCs. Importantly, we demonstrated that miR‐371 cluster, a human homolog of miR‐290 cluster, stimulates glycolysis to promote the reprogramming of human fibroblasts. Hence, we identified a previously unappreciated mechanism by which miR‐290/371 miRNAs orchestrate epigenetic, transcriptional and metabolic networks to promote pluripotency in PSCs and during reprogramming.