MafA, NeuroD1, and HNF1β synergistically activate the Slc2a2 (Glut2) gene in β-cells

in Journal of Molecular Endocrinology
Authors:
Yuka Ono Laboratory of Molecular Medical Bioscience, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan

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Kohsuke Kataoka Laboratory of Molecular Medical Bioscience, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan

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Correspondence should be addressed to K Kataoka: kkataoka@yokohama-cu.ac.jp
DOI:
https://doi.org/10.1530/JME-20-0339
Volume/Issue:
Volume 67: Issue 3
Article Type:
Research Article
Page Range:
71–82
Online Publication Date:
26 Jul 2021
Copyright:
© Society for Endocrinology 2021
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Glucose transporter type 2 (GLUT2), encoded by the SLC2A2 gene, is an essential component of glucose-stimulated insulin secretion in pancreatic islet β-cells. Like that of the gene encoding insulin, expression of the SLC2A2 gene expression is closely linked to β-cell functionality in rodents, but the mechanism by which β-cell-specific expression of SLC2A2 is controlled remains unclear. In this report, to identify putative enhancer elements of the mouse Slc2a2 gene, we examined evolutional conservation of the nucleotide sequence of its genomic locus, together with ChIP-seq data of histone modifications and various transcription factors published in previous studies. Using luciferase reporter assays, we found that an evolutionarily conserved region (ECR) located approximately 40 kbp downstream of the transcription start site of Slc2a2 functions as an active enhancer in the MIN6 β-cell line. We also found that three β-cell-enriched transcription factors, MafA, NeuroD1, and HNF1β, synergistically activate transcription through this 3’ downstream distal enhancer (ECR3’) and the proximal promoter region of the gene. Our data also indicate that the simultaneous binding of HNF1β to its target sites within the promoter and ECR3’ of Slc2a2 is indispensable for transcriptional activation, and that binding of MafA and NeuroD1 to their respective target sites within the ECR3’ enhances transcription. Co-immunoprecipitation experiments suggested that MafA, NeuroD1, and HNF1β interact with each other. Overall, these results suggest that promoter-enhancer communication through MafA, NeuroD1, and HNF1β is critical for Slc2a2 gene expression. These findings provide clues to help elucidate the mechanism of regulation of Slc2a2 gene expression in β-cells.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© Society for Endocrinology 2021
Page(s):
12
Article Type:
Research Article
Received Date:
24 Jun 2021
Accepted Date:
05 Jul 2021
Print Publication Date:
01 Oct 2021
Online Publication Date:
26 Jul 2021
Keywords:
Slc2a2; glucose transporter 2 (glut2); pancreatic β-cell; gene regulation

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