Circadian clock disruption by selective removal of endogenous carbon monoxide

Abstract Circadian rhythms are regulated by transcription-translation feedback loops (TTFL) of clock genes. Previous studies have demonstrated that core transcriptional factors, NPAS2 and CLOCK, in the TTFL can reversibly bind carbon monoxide (CO) in vitro. However, little is known about whether end...

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Autores principales:	Saika Minegishi, Ikuko Sagami, Shigeru Negi, Koji Kano, Hiroaki Kitagishi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/24186bf1afc04da39932da7b83b32754
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spelling	oai:doaj.org-article:24186bf1afc04da39932da7b83b327542021-12-02T15:08:37ZCircadian clock disruption by selective removal of endogenous carbon monoxide10.1038/s41598-018-30425-62045-2322https://doaj.org/article/24186bf1afc04da39932da7b83b327542018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-30425-6https://doaj.org/toc/2045-2322Abstract Circadian rhythms are regulated by transcription-translation feedback loops (TTFL) of clock genes. Previous studies have demonstrated that core transcriptional factors, NPAS2 and CLOCK, in the TTFL can reversibly bind carbon monoxide (CO) in vitro. However, little is known about whether endogenous CO, which is continuously produced during a heme metabolic process, is involved in the circadian system. Here we show that selective removal of endogenous CO in mice considerably disrupts rhythmic expression of the clock genes. A highly selective CO scavenger, hemoCD1, which is a supramolecular complex of an iron(II)porphyrin with a per-O-methyl-β-cyclodextrin dimer, was used to remove endogenous CO in mice. Intraperitoneal administration of hemoCD1 to mice immediately reduced the amount of internal CO. The removal of CO promoted the bindings of NPAS2 and CLOCK to DNA (E-box) in the murine liver, resulting in up-regulation of the E-box-controlled clock genes (Per1, Per2, Cry1, Cry2, and Rev-erbα). Within 3 h after the administration, most hemoCD1 in mice was excreted in the urine, and heme oxygenase-1 (HO-1) was gradually induced in the liver. Increased endogenous CO production due to the overexpression of HO-1 caused dissociation of NPAS2 and CLOCK from E-box, which in turn induced down-regulation of the clock genes. The down-regulation continued over 12 h even after the internal CO level recovered to normal. The late down-regulation was ascribed to an inflammatory response caused by the endogenous CO reduction. The CO pseudo-knockdown experiments provided the clear evidence that endogenous CO contributes to regulation in the mammalian circadian clock.Saika MinegishiIkuko SagamiShigeru NegiKoji KanoHiroaki KitagishiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Saika Minegishi Ikuko Sagami Shigeru Negi Koji Kano Hiroaki Kitagishi Circadian clock disruption by selective removal of endogenous carbon monoxide
description	Abstract Circadian rhythms are regulated by transcription-translation feedback loops (TTFL) of clock genes. Previous studies have demonstrated that core transcriptional factors, NPAS2 and CLOCK, in the TTFL can reversibly bind carbon monoxide (CO) in vitro. However, little is known about whether endogenous CO, which is continuously produced during a heme metabolic process, is involved in the circadian system. Here we show that selective removal of endogenous CO in mice considerably disrupts rhythmic expression of the clock genes. A highly selective CO scavenger, hemoCD1, which is a supramolecular complex of an iron(II)porphyrin with a per-O-methyl-β-cyclodextrin dimer, was used to remove endogenous CO in mice. Intraperitoneal administration of hemoCD1 to mice immediately reduced the amount of internal CO. The removal of CO promoted the bindings of NPAS2 and CLOCK to DNA (E-box) in the murine liver, resulting in up-regulation of the E-box-controlled clock genes (Per1, Per2, Cry1, Cry2, and Rev-erbα). Within 3 h after the administration, most hemoCD1 in mice was excreted in the urine, and heme oxygenase-1 (HO-1) was gradually induced in the liver. Increased endogenous CO production due to the overexpression of HO-1 caused dissociation of NPAS2 and CLOCK from E-box, which in turn induced down-regulation of the clock genes. The down-regulation continued over 12 h even after the internal CO level recovered to normal. The late down-regulation was ascribed to an inflammatory response caused by the endogenous CO reduction. The CO pseudo-knockdown experiments provided the clear evidence that endogenous CO contributes to regulation in the mammalian circadian clock.
format	article
author	Saika Minegishi Ikuko Sagami Shigeru Negi Koji Kano Hiroaki Kitagishi
author_facet	Saika Minegishi Ikuko Sagami Shigeru Negi Koji Kano Hiroaki Kitagishi
author_sort	Saika Minegishi
title	Circadian clock disruption by selective removal of endogenous carbon monoxide
title_short	Circadian clock disruption by selective removal of endogenous carbon monoxide
title_full	Circadian clock disruption by selective removal of endogenous carbon monoxide
title_fullStr	Circadian clock disruption by selective removal of endogenous carbon monoxide
title_full_unstemmed	Circadian clock disruption by selective removal of endogenous carbon monoxide
title_sort	circadian clock disruption by selective removal of endogenous carbon monoxide
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/24186bf1afc04da39932da7b83b32754
work_keys_str_mv	AT saikaminegishi circadianclockdisruptionbyselectiveremovalofendogenouscarbonmonoxide AT ikukosagami circadianclockdisruptionbyselectiveremovalofendogenouscarbonmonoxide AT shigerunegi circadianclockdisruptionbyselectiveremovalofendogenouscarbonmonoxide AT kojikano circadianclockdisruptionbyselectiveremovalofendogenouscarbonmonoxide AT hiroakikitagishi circadianclockdisruptionbyselectiveremovalofendogenouscarbonmonoxide
_version_	1718388049441718272

Circadian clock disruption by selective removal of endogenous carbon monoxide

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