Pancreatic 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 that Fcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by β-cell-specific FCoR overexpression (FcorKO-βFcor), and exhibit β-to-α-cell conversion. Compared with FcorKO, β-cell-specific Foxo1 knockout in the FcorKO (DKO) led to decreased Arx expression and α-cell mass. Foxo1 binding to Arx promoter led to DNA methyltransferase 3a (Dnmt3a) dissociation, Arx promoter hypomethylation, and increased Arx expression. In contrast, FCoR suppressed Arx through Foxo1 inhibition and Dnmt3a recruitment to Arx promoter and increased Arx promoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic α-cell mass by suppressing Arx expression.

胰腺内分泌细胞发育为分化的α-和β-细胞受到高度调控，并涉及多种转录因子。然而，确定α和β细胞质量的机制尚不清楚。我们先前确定了Foxo1 CoRepressor（FCoR），它通过乙酰化抑制Foxo1。在这里，我们证明Fcor基因敲除小鼠（FcorKO）表现出显着增加的α细胞质量，即主要α细胞调节转录因子Aristaless相关同源异型框（Arx）的表达，可以通过β细胞特异性FCoR过表达（FcorKO-βFcor），并表现出从β到α细胞的转化。与FcorKO相比，β细胞特异性Foxo1FcorKO（DKO）中的基因敲除导致Arx表达和α细胞质量下降。Foxo1绑定到Arx启动子导致DNA甲基转移酶3a（Dnmt3a）分解，Arx启动子低甲基化，并增加了Arx表达。与此相反，FCOR抑制ARX通过Foxo1的抑制和化酶Dnmt3a募集至ARX启动子和增加ARX启动子甲基化。我们的发现表明，FCoR-Foxo1轴可通过抑制Arx表达来调节胰腺α细胞的质量。