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.
| Original language | English |
|---|---|
| Pages (from-to) | 337-348 |
| Number of pages | 12 |
| Journal | Diabetes |
| Volume | 68 |
| Issue number | 2 |
| DOIs | |
| State | Published - 1 Feb 2019 |
Bibliographical note
Funding Information:Acknowledgments. The authors thank Dr. Hail Kim at the Korea Advanced Institute of Science and Technology (Daejeon, Korea) for helpful guidance during the pregnancy studies. The authors apologize for not providing a more comprehensive list of citations, a limitation imposed by journal regulations. Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants (F32-DK102283 to H.A.C.; F32-DK109577 to E.M.W). This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (RRID: SCR_014393 [https://hirnetwork.org/]; DK104119 to K.H.K.; DK104211, DK108120, and DK112232 to A.C.P.; DK106755 to A.C.P.; and R01-DK909570 to R.S.) and the Vanderbilt Diabetes Research and Training Center (NIDDK grant DK20593). Funds from the Larry L. Hillbolm Foundation (2012-D-006-SUP) were provided to S.D. The JDRF, Leona M. and Harry B. Helmsley Charitable Trust, and U.S. Department of Veterans Affairs also support A.C.P. Imaging was performed with National Institutes of Health support from the Vanderbilt University Medical Center Cell Imaging Shared Resource (National Cancer Institute grant CA68485; NIDDK grants DK20593, DK58404, and DK59637; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] grant HD15052; and National Eye Institute grant EY08126), and islet hormone analysis support was by the Vanderbilt University Medical Center Islet Procurement and Analysis Core (NIDDK grant DK20593) and Vanderbilt University Neurochemistry Core (NICHD grant U54-HD-083211). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program at City of Hope (National Institutes of Health grant 2UC4DK098085). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. H.A.C., E.M.W., Y.H., S.D., R.H., L.B., and D.A. performed experiments. H.A.C., E.M.W., Y.H., S.D., R.H., and D.A. prepared figures. H.A.C., E.M.W., Y.H., S.D., R.H., D.A., M.B., K.H.K., A.B., A.C.P., and R.S. approved the final version of the manuscript. H.A.C., E.M.W., Y.H., S.D., R.H., D.A., K.H.K., A.B., A.C.P., and R.S. analyzed data, interpreted the results of experiments, and edited and revised the manuscript. H.A.C., E.M.W., Y.H., and R.S. contributed to the conception and design of the research and drafted the manuscript. R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
The authors thank Dr. Hail Kim at the Korea Advanced Institute of Science and Technology (Daejeon, Korea) for helpful guidance during the pregnancy studies. The authors apologize for not providing a more comprehensive list of citations, a limitation imposed by journal regulations. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants (F32-DK102283 to H.A.C.; F32-DK109577 to E.M.W). This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (RRID: SCR_014393 [https://hirnetwork.org/]; DK104119 to K.H.K.; DK104211, DK108120, and DK112232 to A.C.P.; DK106755 to A.C.P.; and R01-DK909570 to R.S.) and the Vanderbilt Diabetes Research and Training Center (NIDDK grant DK20593). Funds from the Larry L. Hillbolm Foundation (2012-D-006-SUP) were provided to S.D. The JDRF, Leona M. and Harry B. Helmsley Charitable Trust, and U.S. Department of Veterans Affairs also support A.C.P. Imaging was performed with National Institutes of Health support from the Vanderbilt University Medical Center Cell Imaging Shared Resource (National Cancer Institute grant CA68485; NIDDK grants DK20593, DK58404, and DK59637; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] grant HD15052; and National Eye Institute grant EY08126), and islet hormone analysis support was by the Vanderbilt University Medical Center Islet Procurement and Analysis Core (NIDDK grant DK20593) and Vanderbilt University Neurochemistry Core (NICHD grant U54-HD-083211). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program at City of Hope (National Institutes of Health grant 2UC4DK098085).
Publisher Copyright:
© 2018 by the American Diabetes Association.
