摘要：SummaryPancreatic endocrine cell development into differentiated α- and β-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of α- and β-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate thatFcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factorAristaless-related homeobox(Arx), which can be normalized by β-cell-specific FCoR overexpression (FcorKO-βFcor), and exhibit β-to-α-cell conversion. Compared withFcorKO, β-cell-specificFoxo1knockout in theFcorKO (DKO)led to decreasedArxexpression and α-cell mass. Foxo1 binding toArxpromoter led to DNA methyltransferase 3a (Dnmt3a) dissociation,Arxpromoter hypomethylation, and increasedArxexpression. In contrast, FCoR suppressedArxthrough Foxo1 inhibition and Dnmt3a recruitment toArxpromoter and increasedArxpromoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic α-cell mass by suppressingArxexpression.Graphical AbstractDisplay OmittedHighlights•FCoR increases DNA methylation ofArxpromoter and decreasesArxexpression•Loss-of-Fcorincreases conversion from β- to α-cells•FCoR acetylates and inhibits Foxo1 in pancreatic β-cells•Inactivation of Foxo1 facilitates recruitment of Dnmt3a toArxpromoterMolecular Biology; Endocrinology
