title: Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.
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.
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Geula
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Moshitch-Moshkovitz
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Dominissini
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Abed AlFatah
authors.initials: AA
authors.lastname: Mansour
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Kol
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Mali
authors.initials: M
authors.lastname: Salmon-Divon
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Vera
authors.initials: V
authors.lastname: Hershkovitz
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Peer
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nofar
authors.initials: N
authors.lastname: Mor
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yair S
authors.initials: YS
authors.lastname: Manor
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Moshe Shay
authors.initials: MS
authors.lastname: Ben-Haim
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Yunger
authors.affiliation: Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Yishay
authors.initials: Y
authors.lastname: Pinto
authors.affiliation: The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Diego Adhemar
authors.initials: DA
authors.lastname: Jaitin
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sergey
authors.initials: S
authors.lastname: Viukov
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoach
authors.initials: Y
authors.lastname: Rais
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Krupalnik
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Chomsky
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Mirie
authors.initials: M
authors.lastname: Zerbib
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Itay
authors.initials: I
authors.lastname: Maza
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Rechavi
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rada
authors.initials: R
authors.lastname: Massarwa
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. The Department of Pediatrics and the Pediatric Immunology Unit, Rambam Medical Center, and the B. Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Suhair
authors.initials: S
authors.lastname: Hanna
authors.affiliation: The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Erez Y
authors.initials: EY
authors.lastname: Levanon
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Stern-Ginossar
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.
authors.forename: Noa
authors.initials: N
authors.lastname: Novershtern
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Hanna
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001755:Blastocyst / Q000201:enzymology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D020964:Embryo Loss / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D055786:Gene Knockout Techniques; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C010223:N-methyladenosine; D008780:Methyltransferases; C000596366:Mettl3 protein, mouse; D000241:Adenosine