TY - JOUR
T1 - Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity
AU - Cha, Jeeyeon
AU - Tong, Xin
AU - Walker, Emily M.
AU - Dahan, Tehila
AU - Cochrane, Veronica A.
AU - Ashe, Sudipta
AU - Russell, Ronan
AU - Osipovich, Anna B.
AU - Mawla, Alex M.
AU - Guo, Min
AU - Liu, Jin Hua
AU - Loyd, Zachary A.
AU - Huising, Mark O.
AU - Magnuson, Mark A.
AU - Hebrok, Matthias
AU - Dor, Yuval
AU - Stein, Roland
N1 - Publisher Copyright:
Copyright: © 2023, Cha et al.
PY - 2023/8/22
Y1 - 2023/8/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85168515221&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.166386
DO - 10.1172/jci.insight.166386
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C2 - 37606041
AN - SCOPUS:85168515221
SN - 2379-3708
VL - 8
JO - JCI insight
JF - JCI insight
IS - 16
M1 - e166386
ER -