Tuning the mammalian circadian clock: robust synergy of two loops.

The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and syn...

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Autores principales:	Angela Relógio, Pal O Westermark, Thomas Wallach, Katja Schellenberg, Achim Kramer, Hanspeter Herzel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ea52d2b61a004f42b737540956f351b6
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spelling	oai:doaj.org-article:ea52d2b61a004f42b737540956f351b62021-11-18T05:51:43ZTuning the mammalian circadian clock: robust synergy of two loops.1553-734X1553-735810.1371/journal.pcbi.1002309https://doaj.org/article/ea52d2b61a004f42b737540956f351b62011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22194677/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period--a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations.Angela RelógioPal O WestermarkThomas WallachKatja SchellenbergAchim KramerHanspeter HerzelPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 12, p e1002309 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Angela Relógio Pal O Westermark Thomas Wallach Katja Schellenberg Achim Kramer Hanspeter Herzel Tuning the mammalian circadian clock: robust synergy of two loops.
description	The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period--a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations.
format	article
author	Angela Relógio Pal O Westermark Thomas Wallach Katja Schellenberg Achim Kramer Hanspeter Herzel
author_facet	Angela Relógio Pal O Westermark Thomas Wallach Katja Schellenberg Achim Kramer Hanspeter Herzel
author_sort	Angela Relógio
title	Tuning the mammalian circadian clock: robust synergy of two loops.
title_short	Tuning the mammalian circadian clock: robust synergy of two loops.
title_full	Tuning the mammalian circadian clock: robust synergy of two loops.
title_fullStr	Tuning the mammalian circadian clock: robust synergy of two loops.
title_full_unstemmed	Tuning the mammalian circadian clock: robust synergy of two loops.
title_sort	tuning the mammalian circadian clock: robust synergy of two loops.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ea52d2b61a004f42b737540956f351b6
work_keys_str_mv	AT angelarelogio tuningthemammaliancircadianclockrobustsynergyoftwoloops AT palowestermark tuningthemammaliancircadianclockrobustsynergyoftwoloops AT thomaswallach tuningthemammaliancircadianclockrobustsynergyoftwoloops AT katjaschellenberg tuningthemammaliancircadianclockrobustsynergyoftwoloops AT achimkramer tuningthemammaliancircadianclockrobustsynergyoftwoloops AT hanspeterherzel tuningthemammaliancircadianclockrobustsynergyoftwoloops
_version_	1718424763242643456

Tuning the mammalian circadian clock: robust synergy of two loops.

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