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

Aaron D Viny; Robert L Bowman; Yu Liu; Vincent-Philippe Lavallée; Shira E Eisman; Wenbin Xiao; Benjamin H Durham; Anastasia Navitski; Jane Park; Stephanie Braunstein; Besmira Alija; Abdul Karzai; Isabelle S Csete; Matthew Witkin; Elham Azizi; Timour Baslan; Christopher J Ott; Dana Pe'er; Job Dekker; Richard Koche; Ross L Levine

doi:10.1016/j.stem.2019.08.003

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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
Levine, Ross L¹⁰

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.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 10/23/2019 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/31495782

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