Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
Tamaki AraiMasayuki Murata

Abstract

Forkhead box O1 (FOXO1) is an important target for insulin. It is widely accepted that insulin-induced phosphorylation of FOXO1 by Akt leads to its nuclear exclusion and results in the inhibition of FOXO1-mediated transcription of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1 (PCK1) in hepatocytes. However, many results that contradict this model have accumulated. Here, we provide a new mechanism for insulin-dependent repression of FOXO1-mediated transcription. We showed insulin-induced translocation of endogenous Ser256-phosphorylated FOXO1, which is essential for regulation of FOXO1-mediated transcription, from nuclear speckles to the nuclear periphery. This insulin-dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N-methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region. Notably, our results suggest that FOXO1 uses nucleoporin 98 kDa NUP98 for this transcriptional regulation. These results provide a new insight into various FOXO1-mediated transcriptional regulation and FOXO1-mediated essential biological pathways.

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Citations

Jan 24, 2018·Nature Communications·Sílvia Bonàs-GuarchDavid Torrents
Sep 22, 2017·Nucleus·Juliana S CapitanioRichard W Wozniak
Aug 9, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eva LatorreLorna W Harries
Oct 27, 2018·International Journal of Molecular Sciences·Duc-Hiep BachSang Kook Lee
Dec 12, 2018·Nucleic Acids Research·Yun-Cheol ChaeSang-Beom Seo
Jul 6, 2021·Frontiers in Genetics·Jana StichtStefan Konigorski

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