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

AUTHORS

Cha J , Tong X , Walker EM , Dahan T , Cochrane VA , Ashe S , Russell R , Osipovich AB , Mawla AM , Guo M , Liu JH , Loyd ZA , Huising MO , Magnuson MA , Hebrok M , Dor Y , Stein R , . JCI insight. 2023 8 22; 8(16).

PMID: 37606041 [PubMed].

ABSTRACT

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.

Tags: 2023