Abstract
Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation. However, the role of Mel18 (PCGF2) in hematopoiesis is not fully understood and how Mel18 regulates gene transcription in HSCs remains elusive. We found that acute deletion of Mel18 in the hematopoietic compartment significantly increased the frequency of functional HSCs in the bone marrow. Furthermore, we demonstrate that Mel18 inhibits HSC self-renewal and proliferation. RNA-seq studies revealed that HSC self-renewal and proliferation gene signatures are enriched in Mel18−/− hematopoietic stem and progenitors (HSPCs) compared to Mel18+/+ HSPCs. Notably, ATAC-seq revealed increased chromatin accessibility at genes important for HSC self-renewal, whereas CUT&RUN showed decreased enrichment of H2AK119ub1 at genes important for proliferation, leading to increased expression of both Hoxb4 and Cdk4 in Mel18−/− HSPCs. Thus, we demonstrate that Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of genes important for HSC self-renewal and proliferation.
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Data availability
Normalized sequencing data can be accessed from the Gene Expression Omnibus (GSE279249, GSE279250, GSE279251 and GSE279252). Requests for raw sequencing data should be addressed to and will be fulfilled by the corresponding author (YL).
Code availability
No custom code or software was used as part of the data analysis. All packages used are listed in the “Methods” section.
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Acknowledgements
We would like to acknowledge the Flow Cytometry Core, Pathology Core, NU Seq core, Quantitative Data Science Core, and Center for Comparative Medicine at Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center. This work was supported by R01 HL150624, R56 DK119524, R56 AG052501, DoD W81XWH-18-1-0265, and DoD W81XWH-19-1-0575 awards (to YL). This work was supported in part by the Leukemia & Lymphoma Society (LLS) Translational Research Program award 6581-20 and the St. Baldrick’s Foundation Scholar Award (to YL). SC was supported by the LLS Career Development Special Fellow Award, American Society of Hematology (ASH) Research Restart Award, and Lady Tata Memorial International Awards for Research in Leukaemia. SB was supported by a NIH F31 Award F31HL160120.
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WC, SC, and YL designed the research. WC, XL, SB, SX, SV, HC, YY, CB, DH, YJ, MH, TMM, and SC performed the research; WC, SL, JW, FY, SC, and YL analyzed the data and performed the statistical analysis. MLC, HL, PJ, ZG, DP, LCP, and RX provided reagents and constructive advice to the study. WC, SC, and YL wrote the manuscript. All authors read, comment on, and approved the manuscript.
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All methods were performed in accordance with the relevant guidelines and regulations. We have complied with all the relevant ethical regulations for animal testing and research. All animal-related experiments have received ethical approval from both Indiana and Northwestern University Institutional Animal Care and Use Committee (IACUC).
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Cai, W., Liu, X., Barajas, S. et al. Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes. Leukemia 39, 296–307 (2025). https://doi.org/10.1038/s41375-024-02462-w
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DOI: https://doi.org/10.1038/s41375-024-02462-w
