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 Zerbib; Itay Maza; Yoav Rechavi; Rada Massarwa; Suhair Hanna; Ido Amit; Erez Y. Levanon; Ninette Amariglio; Noam Stern-Ginossar; Noa Novershtern; Gideon Rechavi; Jacob H. Hanna

doi:10.1126/science.1261417

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

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1236 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 language	English
Pages (from-to)	1002-1006
Number of pages	5
Journal	Science
Volume	347
Issue number	6225
DOIs	https://doi.org/10.1126/science.1261417
State	Published - 27 Feb 2015
Externally published	Yes

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Geula, S., Moshitch-Moshkovitz, S., Dominissini, D., Mansour, A. A. F., Kol, N., Salmon-Divon, M., Hershkovitz, V., Peer, E., Mor, N., Manor, Y. S., Ben-Haim, M. S., Eyal, E., Yunger, S., Pinto, Y., Jaitin, D. A., Viukov, S., Rais, Y., Krupalnik, V., Chomsky, E., ... Hanna, J. H. (2015). m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science, 347(6225), 1002-1006. https://doi.org/10.1126/science.1261417

@article{6fe1349f5f654468a778f8a449bb37fb,

title = "m6A mRNA methylation facilitates resolution of na{\"i}ve pluripotency toward differentiation",

abstract = "Na{\"i}ve 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 na{\"i}ve pluripotency. Mettl3 knockout preimplantation epiblasts and na{\"i}ve embryonic stem cells are depleted for m6A inmRNAs, yet are viable. However, they fail to adequately terminate their na{\"i}ve 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 na{\"i}ve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence na{\"i}ve and primed pluripotency in an opposing manner.",

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

year = "2015",

month = feb,

day = "27",

doi = "10.1126/science.1261417",

language = "אנגלית",

volume = "347",

pages = "1002--1006",

journal = "Science",

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publisher = "American Association for the Advancement of Science",

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Geula, S, Moshitch-Moshkovitz, S, Dominissini, D, Mansour, AAF, Kol, N, Salmon-Divon, M, Hershkovitz, V, Peer, E, Mor, N, Manor, YS, Ben-Haim, MS, Eyal, E, Yunger, S, Pinto, Y, Jaitin, DA, Viukov, S, Rais, Y, Krupalnik, V, Chomsky, E, Zerbib, M, Maza, I, Rechavi, Y, Massarwa, R, Hanna, S, Amit, I, Levanon, EY, Amariglio, N, Stern-Ginossar, N, Novershtern, N, Rechavi, G & Hanna, JH 2015, 'm⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation', Science, vol. 347, no. 6225, pp. 1002-1006. https://doi.org/10.1126/science.1261417

TY - JOUR

T1 - m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

AU - Geula, Shay

AU - Moshitch-Moshkovitz, Sharon

AU - Dominissini, Dan

AU - Mansour, Abed Al Fatah

AU - Kol, Nitzan

AU - Salmon-Divon, Mali

AU - Hershkovitz, Vera

AU - Peer, Eyal

AU - Mor, Nofar

AU - Manor, Yair S.

AU - Ben-Haim, Moshe Shay

AU - Eyal, Eran

AU - Yunger, Sharon

AU - Pinto, Yishay

AU - Jaitin, Diego Adhemar

AU - Viukov, Sergey

AU - Rais, Yoach

AU - Krupalnik, Vladislav

AU - Chomsky, Elad

AU - Zerbib, Mirie

AU - Maza, Itay

AU - Rechavi, Yoav

AU - Massarwa, Rada

AU - Hanna, Suhair

AU - Amit, Ido

AU - Levanon, Erez Y.

AU - Amariglio, Ninette

AU - Stern-Ginossar, Noam

AU - Novershtern, Noa

AU - Rechavi, Gideon

AU - Hanna, Jacob H.

PY - 2015/2/27

Y1 - 2015/2/27

N2 - 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.

AB - 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.

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U2 - 10.1126/science.1261417

DO - 10.1126/science.1261417

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AN - SCOPUS:84922342926

SN - 0036-8075

VL - 347

SP - 1002

EP - 1006

JO - Science

JF - Science

IS - 6225

ER -

m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

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