vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-55vavilov-4230Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYПолучение и характеристика линий эмбриональных стволовых клеток мыши с нокаутом гена Mcph1 (микроцефалин)Generation and analysis of mouse embryonic stem cells with knockout of the Mcph1 (microcephalin) genehttps://orcid.org/0009-0002-2982-5076ЮнусоваА. М.YunusovaA. M.

Новосибирск

Novosibirsk

anastasiajunusova@gmail.comhttps://orcid.org/0000-0001-5152-9914СмирновА. В.SmirnovA. V.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-7452-8372ШнайдерТ. А.ShnaiderT. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-0226-4213ПристяжнюкИ. Е.PristyazhnukI. E.

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Novosibirsk

КораблёваС. Ю.KorablevaS. Y.

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Novosibirsk

https://orcid.org/0000-0003-0611-0203БаттулинН. Р.BattulinN. R.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationНовосибирский национальный исследовательский государственный университетРоссияNovosibirsk State UniversityRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation202402092024285487494Copyright © Юнусова А.М., Смирнов А.В., Шнайдер Т.А., Пристяжнюк И.Е., Кораблёва С.Ю., Баттулин Н.Р., 20242024Юнусова А.М., Смирнов А.В., Шнайдер Т.А., Пристяжнюк И.Е., Кораблёва С.Ю., Баттулин Н.Р.Yunusova A.M., Smirnov A.V., Shnaider T.A., Pristyazhnuk I.E., Korableva S.Y., Battulin N.R.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4230

Хроматин в ядре клетки распределен не хаотично, а имеет организованную структуру, которая оказывает прямое влияние на функционирование генома. Одними из основных архитектурных белков хроматина в клетках млекопитающих являются консервативные мультисубъединичные белковые комплексы: когезин и конденсины. Эти комплексы способны протягивать петли хроматина, опосредуя контакты между удаленными участками ДНК. Тонкая временная регуляция их активности осуществляется рядом других белков, один из которых – микроцефалин (Mcph1). Mcph1 препятствует взаимодействию конденсина II с хроматином в интерфазе. При нарушении его функции наблюдается масштабная реорганизация хроматина, вызванная аномальной загрузкой конденсина II. Как это сказывается на экспрессии генов, до сих пор неизвестно. В данном исследовании мы создали несколько линий эмбриональных стволовых клеток мыши с нокаутом гена Mcph1, охарактеризовали их и проанализировали профиль экспрессии генов. Аннотация дифференциально экспрессирующихся генов в терминах генной онтологии выявила категории генов, относящиеся к общему метаболизму и функционированию обонятельных рецепторов, но не к регуляции клеточного цикла, описанной ранее для Mcph1. Мы также не обнаружили корреляции между генами, изменившими свою транскрипционную активность после нокаута Mcph1, и вероятностью их локализации на ядерной ламине. Этот результат ставит под сомнение гипотезу о влиянии опосредованной нокаутом Mcph1 архитектуры хроматина на экспрессию генов. Среди негативных эффектов нокаута Mcph1 мы наблюдали множественные хромосомные аберрации, включая нарушения сегрегации хромосом с образованием микроядер, а также слияние хромосом. Это подтверждает описанную в предыдущих исследованиях роль белка Mcph1 в поддержании целостности структуры генома. Мы полагаем, что нокаут Mcph1 может оказаться своеобразным «розеттским камнем», способным расшифровать функции конденсина II в интерфазном ядре. Полученные нами линии эмбриональных стволовых клеток с нокаутом гена Mcph1 могут быть использованы для дальнейшего изучения влияния структурных белков хроматина на экспрессию генов.

Chromatin is not randomly distributed within the nucleus, but organized in a three-dimensional structure that plays a critical role in genome functions. Сohesin and condensins are conserved multi-subunit protein complexes that participate in mammalian genome organization by extruding chromatin loops. The fine temporal regulation of these complexes is facilitated by a number of other proteins, one of which is microcephalin (Mcph1). Mcph1 prevents condensin II from associating with chromatin through interphase. Loss of Mcph1 induces chromosome hypercondensation; it is not clear to what extent this reorganization affects gene expression. In this study, we generated several mouse embryonic stem cell (mESC) lines with knockout of the Mcph1 gene and analyzed their gene expression profile. Gene Ontology analyses of differentially expressed genes (DEGs) after Mcph1 knockout revealed gene categories related to general metabolism and olfactory receptor function but not to cell cycle control previously described for Mcph1. We did not find a correlation between the DEGs and their frequency of lamina association. Thus, this evidence questions the hypothesis that Mcph1 knockout-mediated chromatin reorganization governs gene expression in mESCs. Among the negative effects of Mcph1 knockout, we observed numerous chromosomal aberrations, including micronucleus formation and chromosome fusion. This confirms the role of Mcph1 in maintaining genome integrity described previously. In our opinion, dysfunction of Mcph1 may be a kind of “Rosetta stone” for deciphering the function of condensin II in the interphase nucleus. Thus, the cell lines with knocked-out Mcph1 can be used to further study the influence of chromatin structural proteins on gene expression.

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