m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

Shay Geula, Sharon Moshitch-Moshkovitz, Dan Dominissini, Abed Al Fatah Mansour, Nitzan Kol, Mali Salmon-Divon, Vera Hershkovitz, Eyal Peer, Nofar Mor, Yair S. Manor, Moshe Shay Ben-Haim, Eran Eyal, Sharon Yunger, Yishay Pinto, Diego Adhemar Jaitin, Sergey Viukov, Yoach Rais, Vladislav Krupalnik, Elad Chomsky, Mirie ZerbibItay Maza, Yoav Rechavi, Rada Massarwa, Suhair Hanna, Ido Amit, Erez Y. Levanon, Ninette Amariglio, Noam Stern-Ginossar, Noa Novershtern, Gideon Rechavi, Jacob H. Hanna

Research output: Contribution to journalArticlepeer-review

1263 Scopus citations

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 N6-methyladenosine (m6A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m6A inmRNAs, 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. m6A 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.

Original languageEnglish
Pages (from-to)1002-1006
Number of pages5
JournalScience
Volume347
Issue number6225
DOIs
StatePublished - 27 Feb 2015

Bibliographical note

Publisher Copyright:
© 2015, American Association for the Advancement of Science. All rights reserved.

Funding

FundersFunder number
European CommissionStG-2011-281906
Flight Attendant Medical Research Institute
Human Frontier Science Program
Israel Cancer Research Fund
Israel Science Foundation41/11, 1667/12, 1796/12
Leona M. and Harry B. Helmsley Charitable Trust
New York Stem Cell Foundation

    Fingerprint

    Dive into the research topics of 'm6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation'. Together they form a unique fingerprint.

    Cite this