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

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

Keywords

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

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