The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Science. 2015 Feb 27;347(6225):1002-6. doi: 10.1126/science.1261417. Epub 2015 Jan 1.
Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.
幼稚和初始多能状态保留不同的分子特性，但对于它们的状态转变如何受到调控，目前了解有限。在这里，我们鉴定出 Mettl3，一种 N(6)-甲基腺苷（m(6)A）转移酶，作为终止小鼠幼稚多能性的调节因子。Mettl3 敲除的着床前胚胎外胚层和幼稚胚胎干细胞中 mRNA 的 m(6)A 被耗尽，但仍具有活力。然而，它们不能充分终止其幼稚状态，随后在植入后阶段经历异常和受限的谱系起始，导致早期胚胎致死。m(6)A 主要且直接降低 mRNA 的稳定性，包括关键的幼稚多能性促进转录本的稳定性。这项研究强调了一种 mRNA 表观遗传修饰在体内的关键作用，并确定了调节模块，它们以相反的方式对幼稚和初始多能性产生功能影响。
