m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation
m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation
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DOI：
10.1126/science.1261417
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发表时间：
2015-02-27
期刊：
影响因子：
56.9
通讯作者：
Hanna, Jacob H.
中科院分区：
文献类型：
--
作者：
Geula, Shay;Moshitch-Moshkovitz, Sharon;Hanna, Jacob H.
幼稚和引发的多能状态保留不同的分子特性，但有限的知识存在于如何调节它们的状态转换。在这里，我们确定Mettl 3，一种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剂。Mettl 3敲除的植入前上胚层细胞和幼稚胚胎干细胞在mRNA中耗尽m（6）A，但仍存活。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引发，这导致早期胚胎致死。m（6）A主要和直接降低mRNA稳定性，包括关键的幼稚多能性促进转录物的稳定性。这项研究强调了mRNA表观遗传修饰在体内的关键作用，并确定了调控模块，功能上影响幼稚和引发的多能性，在相反的方式。
Naive 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 naive pluripotency. Mettl3 knockout preimplantation epiblasts and naive embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naive 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 naive pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naive and primed pluripotency in an opposing manner.