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

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.

Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males

“…It is also likely that the human MAFA S64F :MAFB heterodimeric activator will impart a unique influence on β cells compared to the mouse MafA S64F :MafA homodimeric activator (Cyphert et al, 2019;Hang and Stein, 2011), which may explain why neuroendocrine tumors and overt hypoglycemia was not observed in aged MafA S64F/+ mice (data not shown). Notably, MAFB was recently shown to be essential for the formation of human embryonic derived β cells and insulin production (Russell, 2020), whereas there is no phenotype associated with the loss of MafB in mouse islet β cells (i.e.…”

“…(Raum et al, 2006;Raum et al, 2010) Expression of the other large Maf family member produced in the islet, MafB, differs from MafA in being expressed in both murine aand β-cells developmentally (Cyphert et al, 2019;Hang and Stein, 2011), then postnatally only in a cells and a subpopulation of β cells during pregnancy (Banerjee et al, 2016;Cyphert et al, 2019). Moreover, genetic studies have demonstrated that MafB is dispensable in regulating adult murine islet β cell function, except during pregnancy (Banerjee et al, 2016;Cyphert et al, 2019). MafA expression during mouse β cell development compensates for the absence of MafB, although glucagon secretion from islet a cells is compromised (Cyphert et al, 2019).…”

“…Moreover, genetic studies have demonstrated that MafB is dispensable in regulating adult murine islet β cell function, except during pregnancy (Banerjee et al, 2016;Cyphert et al, 2019). MafA expression during mouse β cell development compensates for the absence of MafB, although glucagon secretion from islet a cells is compromised (Cyphert et al, 2019). In addition, mis-expressing MafB in MafA Δpanc β cells cannot rescue MafA function (Cyphert et al, 2019).…”

“…Glucose-stimulated hormone secretion WT and MafA S64F/+ mouse (n = 3-6) islets were isolated using standard islet isolation conditions and used in hormone secretion assays as described previously (Cyphert et al, 2019).…”

In vivo Environment Swiftly Restricts Human Pancreatic Progenitors Toward Mono-Hormonal Identity via a HNF1A/HNF4A Mechanism

“…Unfortunately, due to inherent sensitivity issues related to performing proteomics on encapsulated samples, we were unable to confirm ARX or MAFB decrease as a consequence of MECP2 activation in the transplanted cells. Of note, as MAFB retains its expression in mature human β-cells (Conrad et al, 2016;Cyphert et al, 2019), it is possible that its regulation is not affected in the human context. Interestingly, MECP2 was organically networked with regulated proteins involved in the lipid and energy metabolism (Figure 3F), suggesting a link between the improved energetic status of the transplanted cells and its upregulation.…”