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  • Cell Differentiation/genetics/*physiology  (1)
  • Induced Pluripotent Stem Cells/*physiology  (1)
  • 1
    Publication Date: 2015-01-09
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geula, Shay -- Moshitch-Moshkovitz, Sharon -- Dominissini, Dan -- Mansour, Abed AlFatah -- Kol, Nitzan -- Salmon-Divon, Mali -- Hershkovitz, Vera -- Peer, Eyal -- Mor, Nofar -- Manor, Yair S -- Ben-Haim, Moshe Shay -- Eyal, Eran -- Yunger, Sharon -- Pinto, Yishay -- Jaitin, Diego Adhemar -- Viukov, Sergey -- Rais, Yoach -- Krupalnik, Vladislav -- Chomsky, Elad -- Zerbib, Mirie -- Maza, Itay -- Rechavi, Yoav -- Massarwa, Rada -- Hanna, Suhair -- Amit, Ido -- Levanon, Erez Y -- Amariglio, Ninette -- Stern-Ginossar, Noam -- Novershtern, Noa -- Rechavi, Gideon -- Hanna, Jacob H -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):1002-6. doi: 10.1126/science.1261417. Epub 2015 Jan 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. ; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. ; 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. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25569111" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/metabolism ; Animals ; Blastocyst/enzymology ; Cell Differentiation/genetics/*physiology ; Cell Line ; Embryo Loss/genetics ; Epigenesis, Genetic ; Female ; Gene Knockout Techniques ; Male ; Methylation ; Methyltransferases/genetics/*physiology ; Mice ; Mice, Knockout ; Pluripotent Stem Cells/*cytology/enzymology ; RNA, Messenger/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-09-21
    Description: Somatic cells can be inefficiently and stochastically reprogrammed into induced pluripotent stem (iPS) cells by exogenous expression of Oct4 (also called Pou5f1), Sox2, Klf4 and Myc (hereafter referred to as OSKM). The nature of the predominant rate-limiting barrier(s) preventing the majority of cells to successfully and synchronously reprogram remains to be defined. Here we show that depleting Mbd3, a core member of the Mbd3/NuRD (nucleosome remodelling and deacetylation) repressor complex, together with OSKM transduction and reprogramming in naive pluripotency promoting conditions, result in deterministic and synchronized iPS cell reprogramming (near 100% efficiency within seven days from mouse and human cells). Our findings uncover a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the Mbd3/NuRD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early pre-implantation development in vivo, lead to a stochastic and protracted reprogramming trajectory towards pluripotency in vitro. The deterministic reprogramming approach devised here offers a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rais, Yoach -- Zviran, Asaf -- Geula, Shay -- Gafni, Ohad -- Chomsky, Elad -- Viukov, Sergey -- Mansour, Abed AlFatah -- Caspi, Inbal -- Krupalnik, Vladislav -- Zerbib, Mirie -- Maza, Itay -- Mor, Nofar -- Baran, Dror -- Weinberger, Leehee -- Jaitin, Diego A -- Lara-Astiaso, David -- Blecher-Gonen, Ronnie -- Shipony, Zohar -- Mukamel, Zohar -- Hagai, Tzachi -- Gilad, Shlomit -- Amann-Zalcenstein, Daniela -- Tanay, Amos -- Amit, Ido -- Novershtern, Noa -- Hanna, Jacob H -- England -- Nature. 2013 Oct 3;502(7469):65-70. doi: 10.1038/nature12587. Epub 2013 Sep 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24048479" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Cellular Reprogramming/genetics/*physiology ; DNA-Binding Proteins/genetics ; Embryonic Stem Cells ; Female ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Male ; Mice ; *Models, Biological ; Transcription Factors/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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