BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
Year: 2025
Type: article
Abstract: The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.
Source: Nature Communications
Authors: 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, James Palis
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Yale University, University of Rochester, National Institutes of Health, Medical Center, University of Rochester, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G143768663, G1611013288, Improving transfusion therapy for patients with sickle cell disease with pluripotent stem cell-derived red cells, G1898246894, Cellular and Molecular Control of Normal and Disordered Erythropoiesis, G2664498519, G3235567867, G3256272950, Elucidation of the Role of Setd8 and H4K20me1 in Erythropoiesis, G340342131, Erythroid precursor self-renewal, G4411448324, G4528108327, G5613642273, G5794849327, G5950577451, G625544220, G6879096673, Molecular targeting of erythroid progenitor cells in normal and disordered human erythropoiesis, G9000001345, G9000066862, G9000159197, G9000334637, Investigation into the function of RNA polymerase II promoter proximal pausing during terminal erythroid maturation, Erythroid Self-Renewal
OpenAlex ID: W4413258138