BMI1 regulates human erythroid self-renewal through both gene repression and gene activation

Kathleen E. McGrath, Jayme L. Olsen, Anne D. Koniski, Kristin E. Murphy, Michael Getman, Hyun Hyung An, Vincent P. Schulz, Ah Ram Kim, Bin Zhang, Taylor L. Carlson, Julien Papoin, Lionel Blanc, Paul D. Kingsley, Connie M. Westhoff, Patrick G. Gallagher, Stella T. Chou, Laurie A. Steiner and James Palis ()
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Kathleen E. McGrath: University of Rochester Medical Center
Jayme L. Olsen: University of Rochester Medical Center
Anne D. Koniski: University of Rochester Medical Center
Kristin E. Murphy: University of Rochester Medical Center
Michael Getman: University of Rochester Medical Center
Hyun Hyung An: The Children’s Hospital of Philadelphia
Vincent P. Schulz: Yale School of Medicine
Ah Ram Kim: University of Rochester Medical Center
Bin Zhang: University of Rochester Medical Center
Taylor L. Carlson: University of Rochester Medical Center
Julien Papoin: Feinstein Institutes for Medical Research
Lionel Blanc: Feinstein Institutes for Medical Research
Paul D. Kingsley: University of Rochester Medical Center
Connie M. Westhoff: New York Blood Center
Patrick G. Gallagher: Yale School of Medicine
Stella T. Chou: The Children’s Hospital of Philadelphia
Laurie A. Steiner: University of Rochester Medical Center
James Palis: University of Rochester Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient in vitro-derived red blood cells for clinical purposes. While BMI1, a Polycomb Repressive Complex 1 member, is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts, its mechanism of action remains poorly understood. Here we report that BMI1 overexpression leads to 10 billion-fold increase in self-renewal of human erythroblasts, which can terminally mature and agglutinate with typing reagent monoclonal antibodies. BMI1 and RING1B occupancy, along with repressive histone marks, are present at known BMI1 target genes, including the INK-ARF locus, consistent with altered cell cycle kinetics following BMI1 inhibition. Upregulation of BMI1 target genes with low repressive histone modifications, including key regulators of cholesterol homeostasis, along with functional studies, suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. We conclude that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand immature erythroid precursors for eventual clinical uses.

Date: 2025
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DOI: 10.1038/s41467-025-62993-3

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