m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation

被引：1298

作者：

Geula, Shay ^{[1
]}

Moshitch-Moshkovitz, Sharon ^{[2
,3
]}

Dominissini, Dan ^{[4
,5
]}

Mansour, Abed AlFatah ^{[1
]}

Kol, Nitzan ^{[2
,3
]}

Salmon-Divon, Mali ^{[2
,3
]}

Hershkovitz, Vera ^{[2
,3
]}

Peer, Eyal ^{[2
,3
]}

Mor, Nofar ^{[1
]}

Manor, Yair S. ^{[1
]}

Ben-Haim, Moshe Shay ^{[2
,3
]}

Eyal, Eran ^{[2
,3
]}

Yunger, Sharon ^{[2
,3
]}

Pinto, Yishay ^{[6
]}

Jaitin, Diego Adhemar ^{[7
]}

Viukov, Sergey ^{[1
]}

Rais, Yoach ^{[1
]}

Krupalnik, Vladislav ^{[1
]}

Chomsky, Elad ^{[1
]}

Zerbib, Mirie ^{[1
]}

Maza, Itay ^{[1
]}

Rechavi, Yoav ^{[1
]}

Massarwa, Rada ^{[1
]}

Hanna, Suhair ^{[1
,8
,9
,10
]}

Amit, Ido ^{[7
]}

Levanon, Erez Y. ^{[6
]}

Amariglio, Ninette ^{[2
,3
,6
]}

Stern-Ginossar, Noam ^{[1
]}

Novershtern, Noa ^{[1
]}

Rechavi, Gideon ^{[2
,3
]}

Hanna, Jacob H. ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel

[2] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel

[3] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel

[4] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[5] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[6] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel

[7] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel

[8] Technion Israel Inst Technol, Rambam Med Ctr, Dept Pediat, Haifa, Israel

[9] Technion Israel Inst Technol, Rambam Med Ctr, Pediat Immunol Unit, Haifa, Israel

[10] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel

来源：

SCIENCE | 2015年 / 347卷 / 6225期

基金：

以色列科学基金会; 欧洲研究理事会;

关键词：

STATE;

D O I：

10.1126/science.1261417

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：1002 / 1006

页数：5

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