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A Close Look at β-Cell Transcription Factor Function

Posted by on Tuesday, December 4, 2018 in Discoveries.

Over 27 million people in the United States are living with type 2 (adult onset) diabetes. In most cases, type 2 diabetes results from a mixture of multiple genetic and environmental factors. However, in a small subgroup of patients, mutation of a single gene leads to the form of type 2 diabetes known as maturity onset diabetes of youth. In these cases, the mutated gene encodes one of a number of transcription factors that play a role in islet β-cell development and function. Among these is MAFA, a transcription factor that is present in human β-cells at low levels during childhood but at much higher levels in adults, in contrast to the closely related MAFB, which is expressed strongly throughout life. We rely heavily on animal studies, particularly in mice, to understand the role of transcription factors in β-cell function. This can be problematic in the case of MAFA and MAFB because the pattern of expression of these factors in mice is different from that in humans. Specifically, although both factors are expressed in mouse β cells during embryogenesis, after birth, only MafA is present. This led Vanderbilt Basic Sciences investigators Roland Stein and Alvin Powers along with their laboratories and colleagues in California, Pennsylvania, and Israel to explore the differential functions of MafA and MafB in mouse β-cells. Initial studies confirmed very low expression of MAFA in human β-cells from juveniles, with much stronger expression in adults. Further work identified a region upstream of the transcription start site in the mouse MafBgene that was heavily methylated in β-cells after birth. Methylation of this region, which was catalyzed by the enzyme Dmt3a (de novoDNA methyltransferase 3a), correlated with low expression of the gene. These results helped to explain the low levels of MafB in mouse β-cells. Prior work using mice bearing a deletion mutation of MafAonly in the pancreas revealed defects in β-cell activity and islet architecture. In contrast, transgenic mice that expressed MafB in pancreatic β-cells after birth appeared perfectly normal. Careful biochemical studies confirmed the presence of MafB in the β-cells of these mice, and showed the presence of the protein on the promoters of MafA-regulated genes. As both MafA and MafB function as dimers and can form heterodimers, the researchers concluded that such heterodimers were able to form and function as MafA homodimers in mouse β-cells. Interestingly, although expression of some MafA-regulated genes, such as the gene encoding insulin, was increased in the transgenic mice, the mice did not exhibit a significant change in baseline glucose levels or glucose tolerance. In further work, the researchers crossed the MafB-expressing mice with the mice bearing the MafA deletion in order to determine if MafB could substitute for MafA in β-cells. The results indicated that expression of MafB in the absence of MafA failed to correct for deficits in β-cell function or islet architecture resulting from MafA deficiency. Finally, the researchers explored the one situation in which MafB is expressed in adult mouse β-cells – during pregnancy. In this case, MafB expression leads to proliferation of β-cells and increased insulin secretion as a result of serotonin-dependent signaling. Deletion of MafB during pregnancy leads to glucose intolerance and gestational diabetes in mice. In contrast, transgenic pregnant mice expressing MafB exhibited higher insulin levels, a larger islet β-cell population, and improved glucose tolerance than wild-type pregnant mice. Serotonin levels were higher in the islets of these mice than in controls, a finding that could be attributed to increased expression of Tph1, the gene that encodes the first step in biosynthesis of tryptophan, the precursor of serotonin. In summary, the results confirm the distinct patterns of MafA and MafB expression in mice versus humans, suggest that MafA/MafB heterodimers can function as MafA homodimers in mouse β-cells, at least to some extent, and demonstrate that MafB homodimers cannot substitute for dimers containing MafA. Yet, the findings in pregnant mice suggest a special role for MafB in the pancreas, and the fact that humans express both MAFA and MAFB as adults could relate to the fact that baseline insulin secretion is lower and stimulated secretion higher in humans than in rodents. The work is published in the journal Diabetes [H. A. Cyphert, et al. (2018) Diabetes, published online November 13, DOI: 10.2337/db18-0903].

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