First Author | Kodani N | Year | 2020 |
Journal | iScience | Volume | 23 |
Issue | 1 | Pages | 100798 |
PubMed ID | 31923647 | Mgi Jnum | J:306907 |
Mgi Id | MGI:6717481 | Doi | 10.1016/j.isci.2019.100798 |
Citation | Kodani N, et al. (2020) FCoR-Foxo1 Axis Regulates alpha-Cell Mass through Repression of Arx Expression. iScience 23(1):100798 |
abstractText | Pancreatic endocrine cell development into differentiated alpha- and beta-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of alpha- and beta-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 alpha-cell mass, expression of the master alpha-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by beta-cell-specific FCoR overexpression (FcorKO-betaFcor), and exhibit beta-to-alpha-cell conversion. Compared with FcorKO, beta-cell-specific Foxo1 knockout in the FcorKO (DKO) led to decreased Arx expression and alpha-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 alpha-cell mass by suppressing Arx expression. |