BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
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.
Authors
- Lionel Blanc (ORCID: https://orcid.org/0000-0002-0185-6260)
- Vincent Schulz (ORCID: https://orcid.org/0000-0001-6333-4284)
- Hyun Hyung An (ORCID: https://orcid.org/0000-0002-7070-8552)
- Kathleen E. McGrath (ORCID: https://orcid.org/0000-0002-2372-6109)
- Patrick G. Gallagher (ORCID: https://orcid.org/0000-0002-5424-0224)
- Laurie A. Steiner (ORCID: https://orcid.org/0000-0002-2923-4105)
- Julien Papoin
- Connie M. Westhoff (ORCID: https://orcid.org/0000-0002-1929-4593)
- Anne D. Koniski
- Kristin Murphy
- Bin Zhang (ORCID: https://orcid.org/0000-0002-1671-402X)
- Jayme Olsen
- Paul D. Kingsley (ORCID: https://orcid.org/0000-0003-3997-7436)
- Taylor L. Carlson
- James Palis (ORCID: https://orcid.org/0000-0001-7324-1049)
- Stella T. Chou (ORCID: https://orcid.org/0000-0003-4333-6965)
- Michael Getman (ORCID: https://orcid.org/0000-0003-1669-4812)
- Ah Ram Kim
Institutions
- Nationwide Children's Hospital (US)
- Feinstein Institute for Medical Research (US)
- Children's Hospital of Philadelphia (US)
- New York Blood Center (US)
- University of Rochester Medical Center (US)
- Yale University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1038/s41467-025-62993-3
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Yale University
- University of Rochester
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases