O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors

Zhang, Z.; Huang, Z.; Awad, M.; Elsalanty, M.; Cray, J.; Ball, L. E.; Maynard, J.; Burlingame, A. L.; Zeng, H.; Mansky, K. C.; Ruan, H.-B.

doi:10.1101/2022.12.21.521379

bioRxiv · 10.1101/2022.12.21.521379

O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors

Zhang, Z.·Huang, Z.·Awad, M.·Elsalanty, M.·Cray, J.·Ball, L. E.·Maynard, J.·Burlingame, A. L.·Zeng, H.·Mansky, K. C.·Ruan, H.-B.

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Abstract

In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBP{beta}-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

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Zhang, Z., Huang, Z., Awad, M., Elsalanty, M., Cray, J., Ball, L. E., Maynard, J., Burlingame, A. L., Zeng, H., Mansky, K. C., Ruan, H.-B.. 2022-12-21. O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors. https://doi.org/10.1101/2022.12.21.521379

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