Species-specific roles for the MAFA and MAFB transcription factors in regulatingislet β cell identity

Cha, J.; Tong, X.; Walker, E. M.; Dahan, T.; Cochrane, V.; Ashe, S.; Russell, R.; Osipovich, A. B.; Mawla, A. M.; Guo, M.; Liu, J.-h.; Huising, M. O.; Magnuson, M. A.; Hebrok, M.; Dor, Y.; Stein, R.

doi:10.1101/2022.10.20.512880

bioRxiv · 10.1101/2022.10.20.512880

Species-specific roles for the MAFA and MAFB transcription factors in regulatingislet β cell identity

Cha, J.·Tong, X.·Walker, E. M.·Dahan, T.·Cochrane, V.·Ashe, S.·Russell, R.·Osipovich, A. B.·Mawla, A. M.·Guo, M.·Liu, J.-h.·Huising, M. O.·Magnuson, M. A.·Hebrok, M.·Dor, Y.·Stein, R.

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Abstract

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta ({beta}) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in {beta} cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human {beta} cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D {beta} cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human {beta} cell identity, respectively, by repressing expression of Gast/GAST and other non-{beta} cell hormones.

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Cha, J., Tong, X., Walker, E. M., Dahan, T., Cochrane, V., Ashe, S., Russell, R., Osipovich, A. B., Mawla, A. M., Guo, M., Liu, J.-h., Huising, M. O., Magnuson, M. A., Hebrok, M., Dor, Y., Stein, R.. 2022-10-21. Species-specific roles for the MAFA and MAFB transcription factors in regulatingislet β cell identity. https://doi.org/10.1101/2022.10.20.512880

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