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
N1 - Funding Information:
We thank Dr. Jun-ichi Miyazaki (Osaka University, Osaka, Japan) for providing the CAG-CAT-EGFP mice and pBS II SK (+)-CAG-CAT-EGFP vector, Dr. Ken-ichirou Morohashi and Dr. Kanako Miyabayashi (Kyushu University, Fukuoka, Japan) for providing anti-Arx antibody, Dr. Naoki Mochizuki (National Cerebral and Cardiovascular Center, Osaka, Japan) for providing anti-EGFP antibody, and Dr. Ronald A DePinho (University of Texas MD Anderson Cancer Center, Houston, USA)? and Dr. Domenico Accili (Columbia University, New York, USA) for providing the Foxo1flox/flox mice. This work was supported by Scientific Research on Innovative Areas, a MEXT Grant-in-Aid Project ?Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites? grant numbers 26116724 and JSPS KAKENHI 26670509 to J.N. and by a grant from Nippon Boehringer Ingelheim Co. Ltd. to H.I. J.N. designed the experiments. N.K. M.K. O.K. and J.N. performed the experiments investigating physiological and molecular phenotypes. T.K. prepared the embryonic pancreas samples. N.K. and J.N. wrote the manuscript. H.I. provided detailed comments regarding the manuscript. The authors declare that they have no competing interests.
Funding Information:
We thank Dr. Jun-ichi Miyazaki (Osaka University, Osaka, Japan) for providing the CAG-CAT-EGFP mice and pBS II SK (+)-CAG-CAT-EGFP vector, Dr. Ken-ichirou Morohashi and Dr. Kanako Miyabayashi (Kyushu University, Fukuoka, Japan) for providing anti-Arx antibody, Dr. Naoki Mochizuki (National Cerebral and Cardiovascular Center, Osaka, Japan) for providing anti-EGFP antibody, and Dr. Ronald A DePinho (University of Texas MD Anderson Cancer Center, Houston, USA)
and Dr. Domenico Accili (Columbia University, New York, USA) for providing the Foxo1 flox/flox mice. This work was supported by Scientific Research on Innovative Areas , a MEXT Grant-in-Aid Project "Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites" grant numbers 26116724 and JSPS KAKENHI 26670509 to J.N., and by a grant from Nippon Boehringer Ingelheim Co., Ltd. to H.I.
Publisher Copyright:
© 2019 The Author(s)
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 -