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The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation

View ORCID ProfileAlexander Calderon, Tamara Mestvirishvili, Francesco Boccalatte, Kelly V. Ruggles, Gregory David
doi: https://doi.org/10.1101/2023.01.23.525185
Alexander Calderon
1Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
2Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
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Tamara Mestvirishvili
3Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
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Francesco Boccalatte
4Department of Pathology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
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Kelly V. Ruggles
3Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
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Gregory David
1Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
2Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
5Department of Urology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
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  • For correspondence: gregory.david@nyulangone.org
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Abstract/Summary

To maintain blood homeostasis, millions of terminally differentiated effector cells are produced every day. At the apex of this massive and constant blood production lie hematopoietic stem cells (HSCs), a rare cell type harboring unique self-renewal and multipotent properties. A key feature of HSCs is their ability to temporarily exit the cell cycle in a state termed quiescence. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignant transformation. It is thought that HSCs must re-enter the cell cycle in order to commit to terminal differentiation. However, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Here, we identify the chromatin-associated Sin3B protein as a molecular link between cell cycle progression and differentiation in HSCs. We demonstrate that Sin3B is necessary for HSCs’ commitment to differentiation, but dispensable for their self-renewal or survival. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant cell cycle gene expression, consistent with the observed aberrant progression through the G1 phase of the cell cycle. The defective cell cycle control elicited upon Sin3B inactivation correlates with the engagement of discrete signaling programs, including aberrant expression of cell adhesion molecules and essential components of the interferon signaling cascade in LT-HSCs. Additionally, chromatin accessibility profiling in LT-HSCs reveals the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, suggesting a functional link between cell cycle progression, and priming of hematopoietic stem cells for differentiation. Together, these results point to controlled progression through the G1 phase of the cell cycle as a likely regulator of HSC lineage commitment through the modulation of chromatin features.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Additional data analysis was performed in regard to our ATAC-Seq data, as well as edits to our figures, and additional citations and text added to the main body of the manuscript to more clearly explain our results.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 18, 2023.
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The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation
Alexander Calderon, Tamara Mestvirishvili, Francesco Boccalatte, Kelly V. Ruggles, Gregory David
bioRxiv 2023.01.23.525185; doi: https://doi.org/10.1101/2023.01.23.525185
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The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation
Alexander Calderon, Tamara Mestvirishvili, Francesco Boccalatte, Kelly V. Ruggles, Gregory David
bioRxiv 2023.01.23.525185; doi: https://doi.org/10.1101/2023.01.23.525185

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