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Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.

Authors
  • Viny, Aaron D1
  • Bowman, Robert L2
  • Liu, Yu3
  • Lavallée, Vincent-Philippe4
  • Eisman, Shira E2
  • Xiao, Wenbin5
  • Durham, Benjamin H5
  • Navitski, Anastasia2
  • Park, Jane6
  • Braunstein, Stephanie2
  • Alija, Besmira2
  • Karzai, Abdul2
  • Csete, Isabelle S2
  • Witkin, Matthew6
  • Azizi, Elham4
  • Baslan, Timour7
  • Ott, Christopher J8
  • Pe'er, Dana4
  • Dekker, Job9
  • Koche, Richard6
  • And 1 more
  • 1 Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. , (Mali)
  • 2 Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. , (Mali)
  • 3 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 4 Center for Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. , (Mali)
  • 6 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
  • 10 Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected] , (Mali)
Type
Published Article
Journal
Cell stem cell
Publication Date
Aug 30, 2019
Identifiers
DOI: 10.1016/j.stem.2019.08.003
PMID: 31495782
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation. Copyright © 2019 Elsevier Inc. All rights reserved.

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