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Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency.
Mor, Nofar; Rais, Yoach; Sheban, Daoud; Peles, Shani; Aguilera-Castrejon, Alejandro; Zviran, Asaf; Elinger, Dalia; Viukov, Sergey; Geula, Shay; Krupalnik, Vladislav; Zerbib, Mirie; Chomsky, Elad; Lasman, Lior; Shani, Tom; Bayerl, Jonathan; Gafni, Ohad; Hanna, Suhair; Buenrostro, Jason D; Hagai, Tzachi; Masika, Hagit; Vainorius, Gintautas; Bergman, Yehudit; Greenleaf, William J; Esteban, Miguel A; Elling, Ulrich; Levin, Yishai; Massarwa, Rada; Merbl, Yifat; Novershtern, Noa; Hanna, Jacob H.
Affiliation
  • Mor N; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Rais Y; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel. Electronic address: yoach.rais@gmail.com.
  • Sheban D; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Peles S; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Aguilera-Castrejon A; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Zviran A; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel; New York Genome Center, New York, NY, USA.
  • Elinger D; The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
  • Viukov S; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Geula S; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Krupalnik V; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Zerbib M; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Chomsky E; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
  • Lasman L; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Shani T; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Bayerl J; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Gafni O; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Hanna S; Department of Pediatrics, Rambam Health Care Campus, Haifa, Israel.
  • Buenrostro JD; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
  • Hagai T; EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, UK.
  • Masika H; Department of Developmental Biology and Cancer Research, Hebrew University, Jerusalem, Israel.
  • Vainorius G; Institute of Molecular Biotechnology (IMBA), Vienna, Austria.
  • Bergman Y; Department of Developmental Biology and Cancer Research, Hebrew University, Jerusalem, Israel.
  • Greenleaf WJ; Department of Genetics, Stanford University, Palo Alto, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • Esteban MA; Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • Elling U; Institute of Molecular Biotechnology (IMBA), Vienna, Austria.
  • Levin Y; The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
  • Massarwa R; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel.
  • Merbl Y; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • Novershtern N; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel. Electronic address: noa.novershtern@weizmann.ac.il.
  • Hanna JH; Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel. Electronic address: jacob.hanna@weizmann.ac.il.
Cell Stem Cell ; 23(3): 412-425.e10, 2018 09 06.
Article in En | MEDLINE | ID: mdl-30122475
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / DNA Helicases / DNA-Binding Proteins / GATA Transcription Factors / Induced Pluripotent Stem Cells / Mi-2 Nucleosome Remodeling and Deacetylase Complex Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Stem Cell Year: 2018 Type: Article Affiliation country: Israel
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / DNA Helicases / DNA-Binding Proteins / GATA Transcription Factors / Induced Pluripotent Stem Cells / Mi-2 Nucleosome Remodeling and Deacetylase Complex Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Stem Cell Year: 2018 Type: Article Affiliation country: Israel