Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally
Year: 2018
Type: article
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.
Source: Diabetes
DOI: 10.2337/db18-0903
Institutions: Vanderbilt University, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Vanderbilt University Medical Center, Hadassah Medical Center, University of Pennsylvania, University of California, San Francisco, United States Department of Veterans Affairs, VA Tennessee Valley Healthcare System
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Larry L. Hillblom Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation United Kingdom, Human Islet Research Network, National Institutes of Health, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Eunice Kennedy Shriver Intellectual and Developmental Disability Research Center, G150953014, G1775540164, G1837206581, Human Islet Distribution Coordinating Center, G2371664783, G2588140055, G2703204958, Vanderbilt Mouse Metabolic Phenotyping Center, G3426021646, G35732448, Vanderbilt Mouse Metabolic Phenotyping Center, G4513176822, G4867790825, G497317106, Analyzing the importance of the MAFB transcription factor in human beta cell activity, Molecular Mechanisms of Physiologic Beta Cell Growth in Juvenile Human Pancreas, Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at Vanderbilt University, Characterization of Human MafA/B Activity in Pancreatic Beta Cells, G5959661852, G6845279160, Integrated Program for Human Pancreas Procurement and Analysis, Discovery of Pancreatic Signatures in Type 2 Diabetes Mellitus, High-resolution analysis of juvenile human pancreas maturation, Epigenetic Rejuvenation of Human Beta-Cells, Molecular and Cellular Basis for Digestive Diseases, Integrated Islet Distribution Program (U24) - 2021, Cancer Center Support Grant, Vanderbilt Diabetes Research Center, Core Grant in Vision Research, Defining the role of MafA in islet beta cells, G94474260
OpenAlex ID: W2901205495