vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-94vavilov-4408Research ArticleЭВОЛЮЦИОННАЯ БИОЛОГИЯEVOLUTIONARY BIOLOGYРеконструкция и компьютерный анализ структурно-функциональной организации генной сети регуляции биосинтеза холестерина у человека и эволюционная характеристика участвующих в ней геновReconstruction and computer analysis of the structural and functional organization of the gene network regulating cholesterol biosynthesis in humans and the evolutionary characteristics of the genes involved in the networkМихайловаА. Д.MikhailovaA. D.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-3138-381XЛашинС. А.LashinS. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-1859-4631ИванисенкоВ. А.IvanisenkoV. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-9433-8341ДеменковП. С.DemenkovP. S.

Novosibirsk

https://orcid.org/0000-0002-8588-6511ИгнатьеваЕ. В.IgnatievaE. V.

Novosibirsk

eignat@bionet.nsc.ruНовосибирский национальный исследовательский государственный университетРоссияNovosibirsk State UniversityRussian FederationНовосибирский национальный исследовательский государственный университет; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАНРоссияNovosibirsk State University; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Kurchatov Genomic Center of ICG SB RASRussian Federationовосибирский национальный исследовательский государственный университет; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАНРоссияNovosibirsk State University; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Kurchatov Genomic Center of ICG SB RASRussian Federationовосибирский национальный исследовательский государственный университет; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияNovosibirsk State University; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202425012025288864873Copyright © Михайлова А.Д., Лашин С.А., Иванисенко В.А., Деменков П.С., Игнатьева Е.В., 20252025Михайлова А.Д., Лашин С.А., Иванисенко В.А., Деменков П.С., Игнатьева Е.В.Mikhailova A.D., Lashin S.A., Ivanisenko V.A., Demenkov P.S., Ignatieva E.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4408

Холестерин – это незаменимая структурная компонента клеточных мембран, предшественник витамина D и стероидных гормонов. У человека и других видов животных холестерин поступает в организм с пищей, а также синтезируется в клетках многих тканей de novo. Ранее нами была реконструирована генная сеть регуляции внутриклеточного уровня холестерина, включавшая регуляторные контуры, функционирующие при участии транскрипционных факторов подсемейства SREBP (sterol regulatory element-binding proteins). Ак­тивность транскрипционных факторов подсемейства SREBP регулируется в обратной зависимости от уровня холестерина в клетке. Этот механизм реализуется при участии белков «холестеринового сенсора», включаю­щего белки SCAP, INSIG1, INSIG2, MBTPS1/S1P, MBTPS2/S2P и транскрипционные факторы подсемейства SREBP. Повышенный уровень холестерина является фактором риска сердечно-сосудистых заболеваний, а также сопут­ствующим фактором многих патологических состояний. Систематизация сведений о молекулярных механизмах, контролирующих активность факторов подсемейства SREBP и биосинтез холестерина, в формате генной сети и получение новых знаний о генной сети как едином объекте чрезвычайно важны в контексте понимания моле­кулярных механизмов развития заболеваний. Средствами компьютерной системы ANDSystem нами построена генная сеть регуляции биосинтеза холестерина в клетке. Генная сеть включает данные: (1) о ферментах, осущест­вляющих биосинтез холестерина; (2) белках, функционирующих в составе «холестеринового сенсора»; (3) бел­ках, регулирующих активность белков «холестеринового сенсора»; (4) генах, кодирующих белки этих групп; (5) генах, транскрипция которых регулируется при участии транскрипционных факторов подсемейства SREBP (генах-мишенях). Проведен анализ генной сети и выявлены замкнутые регуляторные контуры, контролирующие активность транскрипционных факторов подсемейства SREBP. Эти контуры реализуются с участием генов PPARG, NR0B2/ SHP1, LPIN1, AR и кодируемых ими белков. Исследование филостратиграфического возраста генов показа­ло, что предковые формы большинства генов человека, кодирующих ферменты биосинтеза холестерина и белки «холестеринового сенсора», могли возникнуть на достаточно ранних эволюционных этапах (Cellular organisms (корень филостратиграфического дерева) и этапах дивергенции Eukaryota и Metazoa). Однако механизм регуля­ции транскрипции генов в ответ на изменение уровня холестерина мог сформироваться только на более позд­них эволюционных этапах, поскольку филостратиграфический возраст генов транскрипционных факторов под­семейства SREBP соответствует более позднему этапу эволюции (стадии дивергенции Vertebrata).

Cholesterol is an essential structural component of cell membranes and a precursor of vitamin D, as well as steroid hormones. Humans and other animal species can absorb cholesterol from food. Cholesterol is also syn­thesized de novo in the cells of many tissues. We have previously reconstructed the gene network regulating intra­cellular cholesterol levels, which included regulatory circuits involving transcription factors from the SREBP (Sterol Regulatory Element-Binding Proteins) subfamily. The activity of SREBP transcription factors is regulated inversely depending on the intracellular cholesterol level. This mechanism is implemented with the participation of proteins SCAP, INSIG1, INSIG2, MBTPS1/S1P and MBTPS2/S2P. This group of proteins, together with the SREBP factors, is designated as “cholesterol sensor”. An elevated cholesterol level is a risk factor for the development of cardiovas­cular diseases and may also be observed in obesity, diabetes and other pathological conditions. Systematization of information about the molecular mechanisms controlling the activity of SREBP factors and cholesterol biosyn­thesis in the form of a gene network and building new knowledge about the gene network as a single object is extremely important for understanding the molecular mechanisms underlying the predisposition to diseases. With a computer tool, ANDSystem, we have built a gene network regulating cholesterol biosynthesis. The gene network included data on: (1) the complete set of enzymes involved in cholesterol biosynthesis; (2) proteins that function as part of the “cholesterol sensor”; (3) proteins that regulate the activity of the “cholesterol sensor”; (4) genes encod­ing proteins of these groups; (5) genes whose transcription is regulated by SREBP factors (SREBP target genes). The gene network was analyzed and feedback loops that control the activity of SREBP factors were identified. These feedback loops involved the PPARG, NR0B2/SHP1, LPIN1, and AR genes and the proteins they encode. Analysis of the phylostratigraphic age of the genes showed that the ancestral forms of most human genes encoding the enzymes of cholesterol biosynthesis and the proteins of the “cholesterol sensor” may have arisen at early evolutionary stages (Cellular organisms (the root of the phylostratigraphic tree) and the stages of Eukaryota and Metazoa divergence). However, the mechanism of gene transcription regulation in response to changes in cholesterol levels may only have formed at later evolutionary stages, since the phylostratigraphic age of the genes encoding the transcription factors SREBP1 and SREBP2 corresponds to the stage of Vertebrata divergence.

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