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 language | English |
|---|---|
| Article number | 100798 |
| Journal | iScience |
| Volume | 23 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2020 Jan 24 |
Fingerprint
Keywords
- Endocrinology
- Molecular Biology
ASJC Scopus subject areas
- General
Cite this
FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression. / Kodani, Noriko; Nakae, Jun; Kobayashi, Masaki; Kikuchi, Osamu; Kitamura, Tadahiro; Itoh, Hiroshi.
In: iScience, Vol. 23, No. 1, 100798, 24.01.2020.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression
AU - Kodani, Noriko
AU - Nakae, Jun
AU - Kobayashi, Masaki
AU - Kikuchi, Osamu
AU - Kitamura, Tadahiro
AU - Itoh, Hiroshi
PY - 2020/1/24
Y1 - 2020/1/24
N2 - 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
AB - 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
KW - Endocrinology
KW - Molecular Biology
UR - http://www.scopus.com/inward/record.url?scp=85077370798&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077370798&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2019.100798
DO - 10.1016/j.isci.2019.100798
M3 - Article
AN - SCOPUS:85077370798
VL - 23
JO - iScience
JF - iScience
SN - 2589-0042
IS - 1
M1 - 100798
ER -