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; Jacob H. Hanna

doi:10.1038/nature12587

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 journal › Article › peer-review

429 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 language	English (US)
Pages (from-to)	65-70
Number of pages	6
Journal	Nature
Volume	502
Issue number	7469
DOIs	https://doi.org/10.1038/nature12587
State	Published - 2013
Externally published	Yes

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.

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Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., Baran, D., Weinberger, L., Jaitin, D. A., Lara-Astiaso, D., Blecher-Gonen, R., Shipony, Z., Mukamel, Z., ... Hanna, J. H. (2013). Deterministic direct reprogramming of somatic cells to pluripotency. Nature, 502(7469), 65-70. https://doi.org/10.1038/nature12587

Rais, Y, Zviran, A, Geula, S, Gafni, O, Chomsky, E, Viukov, S, Mansour, AA, Caspi, I, Krupalnik, V, Zerbib, M, Maza, I, Mor, N, Baran, D, Weinberger, L, Jaitin, DA, Lara-Astiaso, D, Blecher-Gonen, R, Shipony, Z, Mukamel, Z, Hagai, T, Gilad, S, Amann-Zalcenstein, D, Tanay, A, Amit, I, Novershtern, N & Hanna, JH 2013, 'Deterministic direct reprogramming of somatic cells to pluripotency', Nature, vol. 502, no. 7469, pp. 65-70. https://doi.org/10.1038/nature12587

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title = "Deterministic direct reprogramming of somatic cells to pluripotency",

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.",

author = "Yoach Rais and Asaf Zviran and Shay Geula and Ohad Gafni and Elad Chomsky and Sergey Viukov and Mansour, {Abed Alfatah} and Inbal Caspi and Vladislav Krupalnik and Mirie Zerbib and Itay Maza and Nofar Mor and Dror Baran and Leehee Weinberger and Jaitin, {Diego A.} and David Lara-Astiaso and Ronnie Blecher-Gonen and Zohar Shipony and Zohar Mukamel and Tzachi Hagai and Shlomit Gilad and Daniela Amann-Zalcenstein and Amos Tanay and Ido Amit and Noa Novershtern and Hanna, {Jacob H.}",

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.",

year = "2013",

doi = "10.1038/nature12587",

language = "English (US)",

volume = "502",

pages = "65--70",

journal = "Nature",

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T1 - Deterministic direct reprogramming of somatic cells to pluripotency

AU - Rais, Yoach

AU - Zviran, Asaf

AU - Geula, Shay

AU - Gafni, Ohad

AU - Chomsky, Elad

AU - Viukov, Sergey

AU - Mansour, Abed Alfatah

AU - Caspi, Inbal

AU - Krupalnik, Vladislav

AU - Zerbib, Mirie

AU - Maza, Itay

AU - Mor, Nofar

AU - Baran, Dror

AU - Weinberger, Leehee

AU - Jaitin, Diego A.

AU - Lara-Astiaso, David

AU - Blecher-Gonen, Ronnie

AU - Shipony, Zohar

AU - Mukamel, Zohar

AU - Hagai, Tzachi

AU - Gilad, Shlomit

AU - Amann-Zalcenstein, Daniela

AU - Tanay, Amos

AU - Amit, Ido

AU - Novershtern, Noa

AU - Hanna, Jacob H.

N1 - 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.

PY - 2013

Y1 - 2013

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AB - 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.

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Deterministic direct reprogramming of somatic cells to pluripotency

Abstract

Bibliographical note

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