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Diabetes. 2019 Feb;68(2):337-348. doi: 10.2337/db18-0903. Epub 2018 Nov 13.

Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.

Author information

1
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
2
Department of Translational Research and Cellular Therapeutics, Beckman Research Institute, City of Hope, Duarte, CA.
3
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
4
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
5
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
6
Diabetes Center, University of California, San Francisco, San Francisco, CA.
7
Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN roland.stein@vanderbilt.edu.

Abstract

The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that MafB expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express MafB in adult mouse β-cells using MafA transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.

PMID:
30425060
PMCID:
PMC6341297
[Available on 2020-02-01]
DOI:
10.2337/db18-0903

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