Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.

JCI insight 2023 Aug 22

filter terms:

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β 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 β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.

Citation

Jeeyeon Cha, Xin Tong, Emily M Walker, Tehila Dahan, Veronica A Cochrane, Sudipta Ashe, Ronan Russell, Anna B Osipovich, Alex M Mawla, Min Guo, Jin-Hua Liu, Zachary A Loyd, Mark O Huising, Mark A Magnuson, Matthias Hebrok, Yuval Dor, Roland Stein. Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity. JCI insight. 2023 Aug 22;8(16)