FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression

Noriko Kodani, Jun Nakae, Masaki Kobayashi, Osamu Kikuchi, Tadahiro Kitamura, Hiroshi Itoh

Research output: Contribution to journalArticle

Abstract

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. Molecular Biology; Endocrinology

Original languageEnglish
Article number100798
JournaliScience
Volume23
Issue number1
DOIs
Publication statusPublished - 2020 Jan 24

Keywords

  • Endocrinology
  • Molecular Biology

ASJC Scopus subject areas

  • General

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    Kodani, N., Nakae, J., Kobayashi, M., Kikuchi, O., Kitamura, T., & Itoh, H. (2020). FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression. iScience, 23(1), [100798]. https://doi.org/10.1016/j.isci.2019.100798