Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells.

Ma Y #, Yao N #, Liu G #, Dong L, Liu Y, Zhang M, Wang F, Wang B, Wei X, Dong H, Wang L, Ji S, Zhang J, Wang Y, Huang Y *, Yu J *.

The EMBO Journal, online publication 17 Dec. 2014, DOI: 10.15252/embj.201489957.  PubMed PMID: 25519956.

Abstract
MicroRNAs play important roles in controlling the embryonic stem cell (ESC) state. Although much is known about microRNAs maintaining ESC state, microRNAs that are responsible for promoting ESC differentiation are less reported. Here, by screening 40 microRNAs pre-selected by their expression patterns and predicted targets in Dgcr8-null ESCs, we identify 14 novel differentiation-associated microRNAs. Among them, miR-27a and miR-24, restrained by c-Myc in ESC, exert their roles of silencing self-renewal through directly target several important pluripotency-associated factors, such as Oct4, Foxo1, Smads. Knockout of all miR-27/24 in ESCs leads to serious deficiency in ESC differentiation in vitro and in vivo. Moreover, depleting of them in mouse embryonic fibroblasts can evidently promote somatic cell reprogramming. Altogether, our findings uncover the essential role of miR-27 and miR-24 in ESC differentiation and also demonstrate novel microRNAs responsible for ESC differentiation.

    本所重点实验室余佳课题组与黄粤课题组合作研究论文“Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells”于2014年12月17日在线发表于The EMBO Journal。该研究鉴定了多个新的能够抑制胚胎干细胞自我更新的microRNA 分子，并发现miR-27a/24 能够靶向抑制胚胎干细胞多能性维持的关键转录因子（Oct4, FoxO1）和信号通路（gp130,Smads），参与促进胚胎干细胞分化及自我更新程序的沉默。利用新颖高效的CRISPR/Cas9 基因组编辑技术我们在胚胎干细胞中将该microRNA 家族位于不同染色体上的两个Cluster 同时敲除，发现胚胎干细胞向中胚层分化的潜能被严重削弱；另外，在胚胎成纤维细胞中抑制miR-27a/24 的表达能够显著提高其生成诱导性多能干细胞（iPSC）的效率。该研究为明确多种microRNA在胚胎干细胞定向分化过程中的功能研究提供了新的思路和策略。余佳课题组的马艳妮副研究员、黄粤课题组的姚南博士（2014年毕业）和刘光助理研究员为该研究论文的共同第一作者。