vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ16.201vavilov-860Research ArticleСистемная биология и моделированиеSystems biology and simulationsМатематическая модель циркадного осциллятора млекопитающих: взаимодействие с системой NAD+/SIRT1 и возрастные изменения экспрессии генов циркадного осциллятораComputational model for mammalian circadian oscillator: interacting with NAD+/SIRT1 pathway and age-related changes in gene expression of circadian oscillatorПодколодныйН. Л.PodkolodnyyN. L.

Новосибирск, Россия

Novosibirsk, Russia

pnl@bionet.nsc.ruТвердохлебН. Н.TverdokhlebN. N.

Новосибирск, Россия

Novosibirsk, Russia

ПодколоднаяО. А.PodkolodnayaO. A.

Новосибирск, Россия

Novosibirsk, Russia

Федеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук» Федеральное государственное бюджетное учреждение науки Институт вычислительной математики и математической геофизики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics SB RAS Institute of Computational Mathematics and Mathematical Geophysics SB RASRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук» Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет»РоссияInstitute of Cytology and Genetics SB RAS Novosibirsk State UniversityRussian FederationФедеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияInstitute of Cytology and Genetics SB RASRussian Federation201602022017206848856Copyright © Подколодный Н.Л., Твердохлеб Н.Н., Подколодная О.А., 20172017Подколодный Н.Л., Твердохлеб Н.Н., Подколодная О.А.Podkolodnyy N.L., Tverdokhleb N.N., Podkolodnaya O.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/860

Исследования последнего десятилетия позволяют по-новому посмотреть на возможную связь между процессами старения и циркадным ритмом. Одно из перспективных направлений в этой области появилось в связи с новыми данными относительно участия NAD+-зависимой деацетилазы гистонов SIRT1 в интеграции путей регуляции циркадного ритма и метаболизма и новой функции NAD+ как «метаболического осциллятора». Представлена модифицированная и расширенная нами наиболее детальная модель циркадного осциллятора, разработанная в 2012 г. J.K. Kim и D.B. Forger. В нее включена дополнительная обратная связь осциллятора с участием генов/белков NAMPT, SIRT1, а также NAM, NAD+. Участие транскрипционного фактора CLOCK/BMAL1 в регуляции транскрипции гена NAMPT определяет соответствующую ритмичность экспрессии мРНК и белка NAMPT. Поскольку фермент, продукт этого гена, является ключевым в пути биосинтеза и рециклирования NAD+, циркадный ритм характерен и для колебания уровня этого кофермента и активности NAD+-зависимой деацетилазы гистонов SIRT1. Деацетилирование этим фер-ментом компонент циркадного осциллятора замыкает обратную связь, опосредуемую этим путем. В частности, среди эффектов SIRT1 в циркадном осцилляторе можно выделить усиление деградации белка Per2, усиление транскрипции гена Bmal1, деацетилирование хроматина регуляторных областей генов циркадного осциллятора в области E-боксов с последующим подавлением транскрипции. Все эти процессы представлены в предложенной нами расширенной модели циркадного осциллятора. На основе экспериментальных данных об изменениях активности SIRT1 и уровня NAD+ с возрастом предпринята попытка исследовать влияние этих возрастных изменений на функционирование циркадного осциллятора. Данные моделирования свидетельствуют о снижении уровня экспрессии ряда генов циркадного осциллятора, в частности Bmal1 и Per2, в старших возрастных группах. Отмечается также увеличение периода циркадных осцилляций. Полученные результаты свидетельствуют, что снижение активности SIRT1, связанное с возрастным нарушением метаболизма NAD+, может быть одной из причин нарушений функционирования циркадного осциллятора в супрахиазматических ядрах. Такие нарушения могут повлечь за собой и нарушения циркадных ритмов организма в целом.

Studies of the last decade reveal a new sight on the possible link between aging processes and circadian rhythm. New data on the role of the NAD+-dependent histone deacetylase SIRT1 in the integration of regulation pathways for circadian rhythms and metabolism as well as data on a new function of the NAD+ as the ”metabolic oscillator” open a promising direction in this area. In the paper we suggested a modification and extension of the most detailed model for the circadian oscillator developed by Kim and Forger (2012). We included the additional feedback of the oscillator which concerns genes/proteins NAMPT, SIRT1, and also NAM, NAD+. The regulation of transcription for gene NAMPT by transcription factor CLOCK/BMAL1 determine the appropriate rhythm of mRNA and protein NAMPT expression. Since an enzyme product of this gene is a key in the pathway of biosynthesis and recycling of NAD+, therefore the circadian rhythm is also characteristic for the fluctuations in the level of this coenzyme and in the activity of NAD+-dependent histone deacetylase SIRT1. The deacetylation of circadian oscillator components by this enzyme closes the feedback mediated through this pathway. In particular, the effects of SIRT1 in circadian oscillator are the gain of degradation of protein Per2, increasing of the gene Bmal1 transcription, deacetylation of chromatin in regulatory regions of circadian oscillator genes in the E-boxes area with subsequent suppression of transcription. We took into account all of these processes in our extended model of the circadian oscillator. Based on the experimental data on the aging changes in the activity of SIRT1 and the level of NAD+, we attempted to study the effect of these age-related changes on the functioning of the circadian oscillator. Simulation data showed a decrease in expression level of several genes of the circadian oscillator, in particular, Bmal1 and Per2, in the older age groups. In addition, our extended model predicted an increase in the period of oscillations. The results indicate that decrease in SIRT1 activity deal with agerelated NAD+ metabolic disorder may be one of the reasons for the circadian oscillator dysfunctions in the suprachiasmatic nuclei. Such disorders may result in a breaking of the circadian rhythms in the body as a whole.

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The authors declare that there are no conflicts of interest present.