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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageAmerican English
Article numbere166386
JournalJCI insight
Volume8
Issue number16
DOIs
StatePublished - 22 Aug 2023

Bibliographical note

Publisher Copyright:
Copyright: © 2023, Cha et al.

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