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 HagaiShlomit Gilad, Daniela Amann-Zalcenstein, Amos Tanay, Ido Amit, Noa Novershtern, Jacob H. Hanna

Research output: Contribution to journalArticlepeer-review

374 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)65-70
Number of pages6
JournalNature
Volume502
Issue number7469
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
Acknowledgements J.H.H. is supported by a generous gift from I. and P. Mantoux; and grants from the Leona M. and Harry B. Helmsley Charitable Trust, ERC (StG-281906) grant, BIRAX initiative, Israel Science Foundation (BIKURA, ICORE and Regular programs), ICRF, Fritz Thyssen Stiftung, The Benoziyo Endowment fund, Alon Scholar Program, and the Clore research prize. I.A is supported by the HFSP Career Development Award,anISF-BikuraandtheERC(StG-309788).A.A.M.issupportedbya Weizmann Dean fellowship. We thank N. Barkai and her group, K. Saha, B. Hendrich, J. Nichols and A. Surani, for reagents and advice. We thank the Weizmann Institute management for providing critical financial and infrastructural support.

Fingerprint Dive into the research topics of 'Deterministic direct reprogramming of somatic cells to pluripotency'. Together they form a unique fingerprint.

Cite this