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STEM CELL BIOLOGY

Chromatin remodeling subunit BRM and valine regulate hematopoietic stem/progenitor cell function and self-renewal via intrinsic and extrinsic effects

Leukemia volume 36, pages 821–833 (2022)Cite this article

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Abstract

Little is known of hematopoietic stem (HSC) and progenitor (HPC) cell self-renewal. The role of Brahma (BRM), a chromatin remodeler, in HSC function is unknown. Bone marrow (BM) from Brm−/− mice manifested increased numbers of long- and short-term HSCs, GMPs, and increased numbers and cycling of functional HPCs. However, increased Brm−/− BM HSC numbers had decreased secondary and tertiary engraftment, suggesting BRM enhances HSC self-renewal. Valine was elevated in lineage negative Brm−/− BM cells, linking intracellular valine with Brm expression. Valine enhanced HPC colony formation, replating of human cord blood (CB) HPC-derived colonies, mouse BM and human CB HPC survival in vitro, and ex vivo expansion of normal mouse BM HSCs and HPCs. Valine increased oxygen consumption rates of WT cells. BRM through CD98 was linked to regulated import of branched chain amino acids, such as valine, in HPCs. Brm−/− LSK cells exhibited upregulated interferon response/cell cycle gene programs. Effects of BRM depletion are less apparent on isolated HSCs compared to HSCs in the presence of HPCs, suggesting cell extrinsic effects on HSCs. Thus, intracellular valine is regulated by BRM expression in HPCs, and the BRM/valine axis regulates HSC and HPC self-renewal, proliferation, and possibly differentiation fate decisions.

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Fig. 1: Increased hematopoietic stem cell (HSC) numbers in Brm-/- mouse bone marrow (BM).
Fig. 2: Diminished self-renewal capacity of HSCs from Brm−/− mice following serial transplantation into secondary and tertiary irradiated mouse recipients.
Fig. 3: Metabolic profiling of lin− BM cells of WT and Brm−/− mice.
Fig. 4: Effects of control diluent, valine or leucine and non-dialyzed (normal) or dialyzed FBS on primary HPC colony formation of normal mouse BM and human CB CD34+ cells.
Fig. 5: Human CB secondary colony formation, and mouse BM HPC survival.
Fig. 6: Valine stimulates respiration in lin− WT BM cells.
Fig. 7: Brm−/− LSK exhibit a transcriptomic profile showing enriched interferon response and cell cycle genes.
Fig. 8: Populations of Brm−/− HPC exert cell extrinsic effects on HSC while valine treatment induces cell intrinsic effects.

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Acknowledgements

These studies were supported by the Public Health Service Grants from the NIH to HEB: R35 HL139599 (Outstanding Investigator Award), R01 DK109188, and U54 DK106846. JR was supported as a postdoctoral fellow by NIH T32 DK007519 (PI HEB). We thank Dr. Ching-Pin Chang for Brm−/− mice.

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  1. These authors contributed equally: Naidu Samisubbu R, Capitano Maegan, Ropa James.

Authors and Affiliations

  1. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Samisubbu R. Naidu

  2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    Maegan Capitano, James Ropa, Scott Cooper, Xinxin Huang & Hal E. Broxmeyer

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Contributions

SRN conceived the project idea and hypothesized the stem cell phenotype in Brm−/− mice, performed metabolism experiments and connected BRM to intracellular valine. MC and SC performed and analyzed in vitro and ex vivo assays characterizing BRM and valine regulation of HSC/HPC including colony assays, phenotyping and expansion assays. MC, SC, and JR performed in vivo analyses of BRM and valine regulation of HSC/HPC. JR performed and analyzed RNA-sequencing and CD98 expression analyses. JR and MC interpreted data and hypothesized the working model connecting valine to BRM in HSC/HPC mechanistically and MC, JR, and SC designed and performed the ex vivo and in vivo experiments to validate this model. XH assisted and performed OCR experiments. SRN, MC, JR, and HEB wrote the paper and drafts of the paper were evaluated by all co-authors. HEB designed experiments, scored colony assays, supervised the study, and acquired funding.

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Correspondence to Samisubbu R. Naidu or Hal E. Broxmeyer.

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HEB is on the Scientific Advisory Board of Elixell Corp, a stem cell company. None of the other authors have conflicts of interest to disclose.

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Naidu, S.R., Capitano, M., Ropa, J. et al. Chromatin remodeling subunit BRM and valine regulate hematopoietic stem/progenitor cell function and self-renewal via intrinsic and extrinsic effects. Leukemia 36, 821–833 (2022). https://doi.org/10.1038/s41375-021-01426-8

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