Deterministic direct reprogramming of somatic cells to pluripotency

Yoach Rais, Asaf Zviran, Shay Geula, Ohad Gafni, Elad Chomsky, Sergey Viukov, Abed AlFatah Mansour, Inbal Caspi, Vladislav Krupalnik, Mirie Zerbib, Itay Maza, Nofar Mor, Dror Baran, Leehee Weinberger, Diego A. Jaitin, David Lara-Astiaso, Ronnie Blecher-Gonen, Zohar Shipony, Zohar Mukamel, Tzachi Hagai, Shlomit Gilad, Daniela Amann-Zalcenstein, Amos Tanay, Ido Amit, Noa Novershtern () and Jacob H. Hanna ()
Additional contact information
Yoach Rais: Weizmann Institute of Science, Rehovot 76100, Israel
Asaf Zviran: Weizmann Institute of Science, Rehovot 76100, Israel
Shay Geula: Weizmann Institute of Science, Rehovot 76100, Israel
Ohad Gafni: Weizmann Institute of Science, Rehovot 76100, Israel
Elad Chomsky: Weizmann Institute of Science, Rehovot 76100, Israel
Sergey Viukov: Weizmann Institute of Science, Rehovot 76100, Israel
Abed AlFatah Mansour: Weizmann Institute of Science, Rehovot 76100, Israel
Inbal Caspi: Weizmann Institute of Science, Rehovot 76100, Israel
Vladislav Krupalnik: Weizmann Institute of Science, Rehovot 76100, Israel
Mirie Zerbib: Weizmann Institute of Science, Rehovot 76100, Israel
Itay Maza: Weizmann Institute of Science, Rehovot 76100, Israel
Nofar Mor: Weizmann Institute of Science, Rehovot 76100, Israel
Dror Baran: Weizmann Institute of Science, Rehovot 76100, Israel
Leehee Weinberger: Weizmann Institute of Science, Rehovot 76100, Israel
Diego A. Jaitin: Weizmann Institute of Science, Rehovot 76100, Israel
David Lara-Astiaso: Weizmann Institute of Science, Rehovot 76100, Israel
Ronnie Blecher-Gonen: Weizmann Institute of Science, Rehovot 76100, Israel
Zohar Shipony: Weizmann Institute of Science, Rehovot 76100, Israel
Zohar Mukamel: Weizmann Institute of Science, Rehovot 76100, Israel
Tzachi Hagai: Weizmann Institute of Science, Rehovot 76100, Israel
Shlomit Gilad: The Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
Daniela Amann-Zalcenstein: The Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
Amos Tanay: Weizmann Institute of Science, Rehovot 76100, Israel
Ido Amit: Weizmann Institute of Science, Rehovot 76100, Israel
Noa Novershtern: Weizmann Institute of Science, Rehovot 76100, Israel
Jacob H. Hanna: Weizmann Institute of Science, Rehovot 76100, Israel

Nature, 2013, vol. 502, issue 7469, 65-70

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/nature12587

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