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. 2015 Feb 27;347(6225):1002-6.
doi: 10.1126/science.1261417. Epub 2015 Jan 1.

Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

Shay Geula  1 , Sharon Moshitch-Moshkovitz  2 , Dan Dominissini  3 , Abed AlFatah Mansour  1 , Nitzan Kol  2 , Mali Salmon-Divon  2 , Vera Hershkovitz  2 , Eyal Peer  2 , Nofar Mor  1 , Yair S Manor  1 , Moshe Shay Ben-Haim  2 , Eran Eyal  2 , Sharon Yunger  2 , Yishay Pinto  4 , Diego Adhemar Jaitin  5 , Sergey Viukov  1 , Yoach Rais  1 , Vladislav Krupalnik  1 , Elad Chomsky  1 , Mirie Zerbib  1 , Itay Maza  1 , Yoav Rechavi  1 , Rada Massarwa  1 , Suhair Hanna  6 , Ido Amit  5 , Erez Y Levanon  4 , Ninette Amariglio  7 , Noam Stern-Ginossar  1 , Noa Novershtern  8 , Gideon Rechavi  9 , Jacob H Hanna  8
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Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

Shay Geula et al. Science. .

Abstract

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.

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