期刊
CELL STEM CELL
卷 23, 期 3, 页码 412-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2018.07.004
关键词
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资金
- ERC [ERC-2016-COG-726497, ERC-2015-PoC-692945]
- Flight Attendant Medical Research Council (FAMRI)
- Israel Science Foundation (ISF-ICORE program)
- Israel Science Foundation (ISF-NFSC program)
- Israel Science Foundation (ISF-INCPM program)
- Israel Science Foundation (ISF-Morasha program)
- Kamin-Yeda Fund
- Minerva Stiftung
- Israel Cancer Research Fund (ICRF) Research Professorship
- EMBO Young Investigator Program (EMBO-YIP)
- Israel MOH
- Israel MOST
- Human Frontiers Science Program (HFSP) [RGY0065/2015]
- Benoziyo Endowment fund
- New York Stem Cell Foundation (NYSCF)
- Helen and Martin Kimmel Institute for Stem Cell Research
- Weizmann - U. Michigan Research Program
- Keckst Center
- EMBO long-term postdoctoral fellowship [ALTF-140-2016]
- Weizmann Institute
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. More-over, 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.
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