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.

    本所重點(diǎn)實(shí)驗室余佳課題組與黃粵課題組合作研究論文“Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells”于2014年12月17日在線(xiàn)發(fā)表于The EMBO Journal。該研究鑒定了多個(gè)新的能夠抑制胚胎干細胞自我更新的microRNA 分子，并發(fā)現miR-27a/24 能夠靶向抑制胚胎干細胞多能性維持的關(guān)鍵轉錄因子（Oct4, FoxO1）和信號通路（gp130,Smads），參與促進(jìn)胚胎干細胞分化及自我更新程序的沉默。利用新穎高效的CRISPR/Cas9 基因組編輯技術(shù)我們在胚胎干細胞中將該microRNA 家族位于不同染色體上的兩個(gè)Cluster 同時(shí)敲除，發(fā)現胚胎干細胞向中胚層分化的潛能被嚴重削弱；另外，在胚胎成纖維細胞中抑制miR-27a/24 的表達能夠顯著(zhù)提高其生成誘導性多能干細胞（iPSC）的效率。該研究為明確多種microRNA在胚胎干細胞定向分化過(guò)程中的功能研究提供了新的思路和策略。余佳課題組的馬艷妮副研究員、黃粵課題組的姚南博士（2014年畢業(yè)）和劉光助理研究員為該研究論文的共同第一作者。