REGγ regulates circadian clock by modulating BMAL1 protein stability

Abstract Endogenous clocks generate rhythms in gene expression, which facilitates the organisms to cope through periodic environmental variations in accordance with 24-h light/dark time. A core question that needs to be elucidated is how such rhythms proliferate throughout the cells and regulate the...

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Autores principales:	Syeda Kubra, Haiyang Zhang, Youwen Si, Xiao Gao, Tianzhen Wang, Linian Pan, Lei Li, Nanzhe Zhong, Junjiang Fu, Bianhong Zhang, Xiaotao Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/95ec2bfeaab64192ba59bcab15a7e6e8
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spelling	oai:doaj.org-article:95ec2bfeaab64192ba59bcab15a7e6e82021-11-07T12:21:33ZREGγ regulates circadian clock by modulating BMAL1 protein stability10.1038/s41420-021-00704-92058-7716https://doaj.org/article/95ec2bfeaab64192ba59bcab15a7e6e82021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00704-9https://doaj.org/toc/2058-7716Abstract Endogenous clocks generate rhythms in gene expression, which facilitates the organisms to cope through periodic environmental variations in accordance with 24-h light/dark time. A core question that needs to be elucidated is how such rhythms proliferate throughout the cells and regulate the dynamic physiology. In this study, we demonstrate the role of REGγ as a new regulator of circadian clock in mice, primary MEF, and SY5Y cells. Assessment of circadian conduct reveals a difference in circadian period, wheel mode, and the ability to acclimate the external light stimulus between WT and KO littermates. Compared to WT mice, REGγ KO mice attain the phase delay behavior upon light shock at early night. During the variation of 12/12 h light/dark (LD) exposure, levels of Per1, Per2, Cry1, Clock, Bmal1, and Rorα circadian genes in suprachiasmatic nucleus are significantly higher in REGγ KO than in WT mice, concomitant with remarkable changes in BMAL1 and PER2 proteins. In cultured cells depleted of REGγ, serum shock induces early response of the circadian genes Per1 and Per2 with the cyclic rhythm maintained. Mechanistic study indicates that REGγ directly degrades BMAL1 by the non-canonical proteasome pathway independent of ATP and ubiquitin. Silencing BMAL1 abrogates the changes in circadian genes in REGγ-deficient cells. However, inhibition of GSK-3β, a known promoter for degradation of BMAL1, exacerbates the action of REGγ depletion. In conclusion, our findings define REGγ as a new factor, which functions as a rheostat of circadian rhythms to mitigate the levels of Per1 and Per2 via proteasome-dependent degradation of BMAL1.Syeda KubraHaiyang ZhangYouwen SiXiao GaoTianzhen WangLinian PanLei LiNanzhe ZhongJunjiang FuBianhong ZhangXiaotao LiNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Syeda Kubra Haiyang Zhang Youwen Si Xiao Gao Tianzhen Wang Linian Pan Lei Li Nanzhe Zhong Junjiang Fu Bianhong Zhang Xiaotao Li REGγ regulates circadian clock by modulating BMAL1 protein stability
description	Abstract Endogenous clocks generate rhythms in gene expression, which facilitates the organisms to cope through periodic environmental variations in accordance with 24-h light/dark time. A core question that needs to be elucidated is how such rhythms proliferate throughout the cells and regulate the dynamic physiology. In this study, we demonstrate the role of REGγ as a new regulator of circadian clock in mice, primary MEF, and SY5Y cells. Assessment of circadian conduct reveals a difference in circadian period, wheel mode, and the ability to acclimate the external light stimulus between WT and KO littermates. Compared to WT mice, REGγ KO mice attain the phase delay behavior upon light shock at early night. During the variation of 12/12 h light/dark (LD) exposure, levels of Per1, Per2, Cry1, Clock, Bmal1, and Rorα circadian genes in suprachiasmatic nucleus are significantly higher in REGγ KO than in WT mice, concomitant with remarkable changes in BMAL1 and PER2 proteins. In cultured cells depleted of REGγ, serum shock induces early response of the circadian genes Per1 and Per2 with the cyclic rhythm maintained. Mechanistic study indicates that REGγ directly degrades BMAL1 by the non-canonical proteasome pathway independent of ATP and ubiquitin. Silencing BMAL1 abrogates the changes in circadian genes in REGγ-deficient cells. However, inhibition of GSK-3β, a known promoter for degradation of BMAL1, exacerbates the action of REGγ depletion. In conclusion, our findings define REGγ as a new factor, which functions as a rheostat of circadian rhythms to mitigate the levels of Per1 and Per2 via proteasome-dependent degradation of BMAL1.
format	article
author	Syeda Kubra Haiyang Zhang Youwen Si Xiao Gao Tianzhen Wang Linian Pan Lei Li Nanzhe Zhong Junjiang Fu Bianhong Zhang Xiaotao Li
author_facet	Syeda Kubra Haiyang Zhang Youwen Si Xiao Gao Tianzhen Wang Linian Pan Lei Li Nanzhe Zhong Junjiang Fu Bianhong Zhang Xiaotao Li
author_sort	Syeda Kubra
title	REGγ regulates circadian clock by modulating BMAL1 protein stability
title_short	REGγ regulates circadian clock by modulating BMAL1 protein stability
title_full	REGγ regulates circadian clock by modulating BMAL1 protein stability
title_fullStr	REGγ regulates circadian clock by modulating BMAL1 protein stability
title_full_unstemmed	REGγ regulates circadian clock by modulating BMAL1 protein stability
title_sort	regγ regulates circadian clock by modulating bmal1 protein stability
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/95ec2bfeaab64192ba59bcab15a7e6e8
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REGγ regulates circadian clock by modulating BMAL1 protein stability

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