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Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions.
Orlando, Luca; Tanasijevic, Borko; Nakanishi, Mio; Reid, Jennifer C; García-Rodríguez, Juan L; Chauhan, Kapil Dev; Porras, Deanna P; Aslostovar, Lili; Lu, Justin D; Shapovalova, Zoya; Mitchell, Ryan R; Boyd, Allison L; Bhatia, Mickie.
Afiliação
  • Orlando L; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Tanasijevic B; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Nakanishi M; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Reid JC; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • García-Rodríguez JL; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Chauhan KD; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Porras DP; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Aslostovar L; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Lu JD; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Shapovalova Z; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Mitchell RR; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Boyd AL; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Bhatia M; McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: mbhatia@mcmaster.ca.
Cell Rep ; 34(10): 108818, 2021 03 09.
Article em En | MEDLINE | ID: mdl-33691101
ABSTRACT
Histone variants (HVs) are a subfamily of epigenetic regulators implicated in embryonic development, but their role in human stem cell fate remains unclear. Here, we reveal that the phosphorylation state of the HV H2A.X (γH2A.X) regulates self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic progenitors. As demonstrated by CRISPR-Cas deletion, H2A.X is essential in maintaining normal hPSC behavior. However, reduced levels of γH2A.X enhances hPSC differentiation toward the hematopoietic lineage with concomitant inhibition of neural development. In contrast, activation and sustained levels of phosphorylated H2A.X enhance hPSC neural fate while suppressing hematopoiesis. This controlled lineage bias correlates to occupancy of γH2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patient-derived leukemic progenitors. Our study demonstrates HVs may serve to regulate pluripotent cell fate and that this biology could be extended to somatic cancer stem cell control.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Histonas / Células-Tronco Pluripotentes / Autorrenovação Celular Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Histonas / Células-Tronco Pluripotentes / Autorrenovação Celular Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article