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

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (ß) 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 ß 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 b 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 ß 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 ß cell identity, respectively, by repressing expression of Gast/GAST and other non-b cell hormones. Overall design: Bulk RNASeq was performed on 4 groups of isolated mouse islets: Male Wildtype, Male MafADb, Female Wildtype and Female MafADb. Each group includes 4 replicates