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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity
Jeeyeon Cha1, Xin Tong2, Emily M Walker2
1Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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.
Insights
Transcription factors MafA and MAFB are crucial for maintaining pancreatic beta cell identity in type 2 diabetes (T2D). Loss of these factors leads to hormone misexpression, a hallmark of dysfunctional beta cells.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Type 2 diabetes (T2D) is linked to impaired pancreatic beta cell identity.
- Beta cells inappropriately produce hormones normally found in other islet cells.
- Transcription factors MAFA and MAFB are vital for maintaining beta cell function.
Purpose of the Study:
- To investigate the role of MAFA and MAFB transcription factors in regulating hormone expression in beta cells.
- To determine if MAFA/MAFB influence the development of a dysfunctional beta cell signature in T2D.
Main Methods:
- Utilized mouse models with beta cell-specific MafA deletion.
- Employed human beta cell lines with MAFB or MAFA deficiency.
- Analyzed gene expression patterns, focusing on hormone production.
- Investigated direct transcriptional regulation of GAST by MAFB.
Main Results:
- MafA deficiency in mouse beta cells led to widespread hormone gene misexpression, resembling gastrin-positive (Gast+) cells.
- Human beta cells lacking MAFB, but not MAFA, exhibited a GAST+ gene expression profile.
- GAST was detected in human T2D beta cells with reduced MAFB levels.
- Human MAFB was shown to directly repress GAST gene transcription.
Conclusions:
- MafA and MAFB play a species-specific role in preserving adult beta cell identity (MafA in mice, MAFB in humans).
- Reduced MAFA/MAFB levels may induce Gast/GAST and other hormone expression, signifying a dysfunctional beta cell phenotype in T2D.
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