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 Masika; Gintautas Vainorius; Yehudit Bergman; William J. Greenleaf; Miguel A. Esteban; Ulrich Elling; Yishai Levin; Rada Massarwa; Yifat Merbl; Noa Novershtern; Jacob H. Hanna

doi:10.1016/j.stem.2018.07.004

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 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 language	English
Pages (from-to)	412-425.e10
Journal	Cell Stem Cell
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2018.07.004
State	Published - 6 Sep 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.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

CHD4
Gatad2a
Mbd3
NuRD
P66α
epigenetics
iPSCs
pluripotency
reprogramming

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2018.07.004

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Mor, N., Rais, Y., Sheban, D., Peles, S., Aguilera-Castrejon, A., Zviran, A., Elinger, D., Viukov, S., Geula, S., Krupalnik, V., Zerbib, M., Chomsky, E., Lasman, L., Shani, T., Bayerl, J., Gafni, O., Hanna, S., Buenrostro, J. D., Hagai, T., ... Hanna, J. H. (2018). Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency. Cell Stem Cell, 23(3), 412-425.e10. https://doi.org/10.1016/j.stem.2018.07.004

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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.",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = sep,

day = "6",

doi = "10.1016/j.stem.2018.07.004",

language = "אנגלית",

volume = "23",

pages = "412--425.e10",

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Mor, N, Rais, Y, Sheban, D, Peles, S, Aguilera-Castrejon, A, Zviran, A, Elinger, D, Viukov, S, Geula, S, Krupalnik, V, Zerbib, M, Chomsky, E, Lasman, L, Shani, T, Bayerl, J, Gafni, O, Hanna, S, Buenrostro, JD, Hagai, T, Masika, H, Vainorius, G, Bergman, Y, Greenleaf, WJ, Esteban, MA, Elling, U, Levin, Y, Massarwa, R, Merbl, Y, Novershtern, N & Hanna, JH 2018, 'Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency', Cell Stem Cell, vol. 23, no. 3, pp. 412-425.e10. https://doi.org/10.1016/j.stem.2018.07.004

TY - JOUR

T1 - Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency

AU - Mor, Nofar

AU - Rais, Yoach

AU - Sheban, Daoud

AU - Peles, Shani

AU - Aguilera-Castrejon, Alejandro

AU - Zviran, Asaf

AU - Elinger, Dalia

AU - Viukov, Sergey

AU - Geula, Shay

AU - Krupalnik, Vladislav

AU - Zerbib, Mirie

AU - Chomsky, Elad

AU - Lasman, Lior

AU - Shani, Tom

AU - Bayerl, Jonathan

AU - Gafni, Ohad

AU - Hanna, Suhair

AU - Buenrostro, Jason D.

AU - Hagai, Tzachi

AU - Masika, Hagit

AU - Vainorius, Gintautas

AU - Bergman, Yehudit

AU - Greenleaf, William J.

AU - Esteban, Miguel A.

AU - Elling, Ulrich

AU - Levin, Yishai

AU - Massarwa, Rada

AU - Merbl, Yifat

AU - Novershtern, Noa

AU - Hanna, Jacob H.

PY - 2018/9/6

Y1 - 2018/9/6

N2 - 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.

AB - 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.

KW - CHD4

KW - Gatad2a

KW - Mbd3

KW - NuRD

KW - P66α

KW - epigenetics

KW - iPSCs

KW - pluripotency

KW - reprogramming

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U2 - 10.1016/j.stem.2018.07.004

DO - 10.1016/j.stem.2018.07.004

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C2 - 30122475

AN - SCOPUS:85052631551

SN - 1934-5909

VL - 23

SP - 412-425.e10

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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