Embryonic Vitamin D Deficiency Programs Hematopoietic Stem Cells to Induce Type 2 Diabetes

Bernal-Mizrachi, C.; Oh, J.; Riek, A. E.; Bauerle, K. T.; Dusso, A.; McNerney, K.; Barve, R.; Darwech, I.; Sprague, J.; Moynihan, C.; Zhang, R. M.; Wang, T.; Xing, X.; Li, D.; Head, R. D.; Bambouskova, M.; Mrad, M.; Collins, A.; Sands, M. S.

doi:10.1101/2022.09.08.507174

bioRxiv · 10.1101/2022.09.08.507174

Embryonic Vitamin D Deficiency Programs Hematopoietic Stem Cells to Induce Type 2 Diabetes

Bernal-Mizrachi, C.·Oh, J.·Riek, A. E.·Bauerle, K. T.·Dusso, A.·McNerney, K.·Barve, R.·Darwech, I.·Sprague, J.·Moynihan, C.·Zhang, R. M.·Wang, T.·Xing, X.·Li, D.·Head, R. D.·Bambouskova, M.·Mrad, M.·Collins, A.·Sands, M. S.

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Abstract

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induces diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic subunit alpha and AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

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Bernal-Mizrachi, C., Oh, J., Riek, A. E., Bauerle, K. T., Dusso, A., McNerney, K., Barve, R., Darwech, I., Sprague, J., Moynihan, C., Zhang, R. M., Wang, T., Xing, X., Li, D., Head, R. D., Bambouskova, M., Mrad, M., Collins, A., Sands, M. S.. 2022-09-12. Embryonic Vitamin D Deficiency Programs Hematopoietic Stem Cells to Induce Type 2 Diabetes. https://doi.org/10.1101/2022.09.08.507174

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