Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency

Nofar Mor, Yoach Rais, Daoud Sheban, Shani Peles, Alejandro Aguilera-Castrejon, Asaf Zviran, Dalia Elinger, Sergey Viukov, Shay Geula, Vladislav Krupalnik, Mirie Zerbib, Elad Chomsky, Lior Lasman, Tom Shani, Jonathan Bayerl, Ohad Gafni, Suhair Hanna, Jason D. Buenrostro, Tzachi Hagai, Hagit MasikaGintautas Vainorius, Yehudit Bergman, William J. Greenleaf, Miguel A. Esteban, Ulrich Elling, Yishai Levin, Rada Massarwa, Yifat Merbl, Noa Novershtern, Jacob H. Hanna

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Mbd3, a member of nucleosome remodeling and deacetylase (NuRD) co-repressor complex, was previously identified as an inhibitor for deterministic induced pluripotent stem cell (iPSC) reprogramming, where up to 100% of donor cells successfully complete the process. NuRD can assume multiple mutually exclusive conformations, and it remains unclear whether this deterministic phenotype can be attributed to a specific Mbd3/NuRD subcomplex. Moreover, since complete ablation of Mbd3 blocks somatic cell proliferation, we aimed to explore functionally relevant alternative ways to neutralize Mbd3-dependent NuRD activity. We identify Gatad2a, a NuRD-specific subunit, whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC differentiation and reprogramming without ablating somatic cell proliferation. Inhibition of Gatad2a facilitates deterministic murine iPSC reprogramming within 8 days. We validate a distinct molecular axis, Gatad2a-Chd4-Mbd3, within Mbd3/NuRD as being critical for blocking reestablishment of naive pluripotency and further highlight signaling-dependent and post-translational modifications of Mbd3/NuRD that influence its interactions and assembly. Optimized partial depletion of Mbd3 had been implicated in deterministic reprogramming. Hanna and colleagues now dissect the subcomplex within Mbd3/NuRD that underlies this outcome. Gatad2a is identified as a flexible component that can be entirely ablated without compromising somatic cell proliferation and yet still similarly yields deterministic mouse iPSC formation.

Original languageEnglish (US)
Pages (from-to)412-425.e10
JournalCell Stem Cell
Volume23
Issue number3
DOIs
StatePublished - Sep 6 2018

Bibliographical note

Funding Information:
J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux and research grants from the ERC (ERC-2016-COG-726497; CellNaivety and ERC-2015-PoC-692945; FORMAT), Flight Attendant Medical Research Council (FAMRI), Israel Science Foundation (ISF-ICORE, ISF-NFSC, ISF-INCPM, and ISF-Morasha programs (also to N.N.)), Kamin-Yeda Fund, Minerva Stiftung, the Israel Cancer Research Fund (ICRF) Research Professorship, EMBO Young Investigator Program (EMBO-YIP), Israel MOH, Israel MOST, the Human Frontiers Science Program (HFSP) (RGY0065/2015), the Benoziyo Endowment fund, the New York Stem Cell Foundation (NYSCF), the Helen and Martin Kimmel Institute for Stem Cell Research, the Kimmel Prize by the Weizmann Institute, the Weizmann - U. Michigan Research Program, and the Keckst Center. A.Z. is supported by an EMBO long-term postdoctoral fellowship (ALTF-140-2016). J.H.H. is an NYSCF-Robertson Investigator. We thank the Weizmann Institute management and board for providing critical financial and infrastructural support.

Funding Information:
J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux and research grants from the ERC ( ERC-2016-COG-726497 ; CellNaivety and ERC-2015-PoC-692945 ; FORMAT), Flight Attendant Medical Research Council (FAMRI) , Israel Science Foundation (ISF-ICORE, ISF-NFSC, ISF-INCPM, and ISF-Morasha programs (also to N.N.)), Kamin-Yeda Fund, Minerva Stiftung , the Israel Cancer Research Fund (ICRF) Research Professorship, EMBO Young Investigator Program (EMBO-YIP), Israel MOH , Israel MOST , the Human Frontiers Science Program (HFSP) ( RGY0065/2015 ), the Benoziyo Endowment fund, the New York Stem Cell Foundation (NYSCF) , the Helen and Martin Kimmel Institute for Stem Cell Research , the Kimmel Prize by the Weizmann Institute, the Weizmann - U. Michigan Research Program, and the Keckst Center . A.Z. is supported by an EMBO long-term postdoctoral fellowship (ALTF-140-2016). J.H.H. is an NYSCF-Robertson Investigator. We thank the Weizmann Institute management and board for providing critical financial and infrastructural support.

Keywords

  • CHD4
  • Gatad2a
  • Mbd3
  • NuRD
  • P66α
  • epigenetics
  • iPSCs
  • pluripotency
  • reprogramming

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