vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-94vavilov-5301Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSОсобенности метилирования ДНК в пораженных тканях аорты при дилатации/аневризме и расслоении восходящего отделаDNA methylation analysis of aortic wall tissue in ascending aortic dilatation/aneurysm and dissectionГончароваИ. А.GoncharovaI. A.

Томск

Tomsk

irina.goncharova@medgenetics.ruЗарубинА. А.ZarubinA. A.

Томск

Tomsk

МарковА. В.MarkovA. V.

Томск

Tomsk

ШипулинаС. А.ShipulinaS. A.

Томск

Tomsk

БабушкинаН. П.BabushkinaN. P.

Томск

Tomsk

КоролёваЮ. А.KorolevaIu. A.

Томск

Tomsk

СлепцовА. А.SleptcovA. A.

Томск

Tomsk

НазаренкоМ. С.NazarenkoM. S.

Томск

Tomsk

Научно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation202613102026306938948Copyright © Гончарова И.А., Зарубин А.А., Марков А.В., Шипулина С.А., Бабушкина Н.П., Королёва Ю.А., Слепцов А.А., Назаренко М.С., 20262026Гончарова И.А., Зарубин А.А., Марков А.В., Шипулина С.А., Бабушкина Н.П., Королёва Ю.А., Слепцов А.А., Назаренко М.С.Goncharova I.A., Zarubin A.A., Markov A.V., Shipulina S.A., Babushkina N.P., Koroleva I.A., Sleptcov A.A., Nazarenko M.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5301

Дилатация/аневризма и расслоение восходящей аорты относятся к жизнеугрожающим заболеваниям, и выявление эпигенетического ландшафта, регулирующего функционирование генома в клетках аорты при данной патологии, является актуальной задачей. В связи с этим в настоящем исследовании выполнена идентификация дифференциально метилированных генов (ДМГ) в тканях аорты при дилатации/аневризме и расслоении восходящего отдела с помощью реанализа данных по метилированию ДНК, представленных в открытом доступе в репозитории NCBI GEO (Gene Expression Omnibus). Проведен реанализ результатов исследований (GSE50192, GSE202047, GSE84274), реализованных на платформе Illumina Infinium HumanMethylation450 BeadChip. Биоинформатическая деконволюция клеточного состава тканей сосудов осуществлена с помощью алгоритма HEpiDISH, а также разработанного референса, включавшего набор CpG-сайтов, индекс метилирования которых специфичен для эндотелиальных клеток, фибробластов, гладкомышечных и иммунных клеток. Реанализ данных показал, что расслоение аорты и ее дилатация/ аневризма с двухстворчатым аортальным клапаном характеризуются специфическим профилем метилирования ДНК относительно интактной ткани аорты, поскольку различаются как по числу, так и по спектру ДМГ. Поправка на клеточный состав аннулирует основное количество ДМГ, но позволяет составить представление о наличии воспаления в ткани аорты, оцениваемого по степени инфильтрации ткани иммунными клетками, охарактеризовать роль воспалительного инфильтрата в нарушении целостности стенки аорты и выявить гены, отражающие различия, связанные с изучаемыми фенотипами, а не с межгрупповой гетерогенностью клеточных популяций. Гены NFIX, PCDH7, MED13L, LMO4, DIP2C, PLEKHF1, NKD1, C10orf41 (ZNF503-AS2), ARAP2, TBX3, TBX5, оставшиеся в статусе ДМГ после поправки на клеточный состав и экспрессируемые в отдельных клетках/цельной ткани аорты, могут рассматриваться как новые гены-кандидаты развития дилатации/аневризмы аорты у пациентов с двухстворчатым аортальным клапаном. Белковые продукты генов NFIX, LMO4, DIP2C, C10orf41 (ZNF503-AS2), MED13L, TBX3 и TBX5 являются транскрипционными факторами или регуляторами транскрипционной активности ДНК, а гена NKD1 – ингибитором сигнального пути Wnt. Полученные данные подчеркивают необходимость строгого подхода к формированию групп сравнения с полным описанием исследуемого фенотипа, включающим морфологию аортального клапана, и проведения исследований на уровне отдельных клеток.

Ascending aortic dilatation/aneurysm and dissection are life-threatening cardiovascular conditions. However, the epigenetic regulatory mechanisms within aortic cells underlying these pathologies remain poorly understood. This study aimed to identify differentially methylated genes (DMGs) in aortic tissues from patients with ascending aortic dilatation/ aneurysm and dissection by performing a re-analysis of publicly available DNA methylation datasets. A re-analysis was conducted on three DNA methylation datasets (GSE50192, GSE202047, GSE84274) from the Illumina Infinium HumanMethylation450 BeadChip. To account for tissue heterogeneity, cellular deconvolution was performed using the HEpiDISH algorithm and a custom reference panel of cell-type-specific CpG sites for key vascular cell types (endothelial cells, fibroblasts, smooth muscle cells, immune cells). Our re-analysis revealed that aortic dissection and bicuspid aortic valve patients with aortic dilatation/aneurysm exhibit distinct DNA methylation profiles compared to intact aorta. These pathologies differ from each other in the number and the spectrum of DMGs. The adjustment for cellular heterogeneity eliminated the majority of the initially identified DMGs. However, this correction helped to make an assessment of vascular inflammation, characterize its impact on aortic wall stability, and identify genes with differential DNA methylation associated with the disease phenotypes, rather than with inter-group heterogeneity. The genes NFIX, PCDH7, MED13L, LMO4, DIP2C, PLEKHF1, NKD1, C10orf41 (ZNF503-AS2), ARAP2, TBX3, and TBX5, which remained in the DMG status after adjustment for cellular composition and are expressed in individual cells/whole aortic tissue, can be considered as new candidate genes for the development of aortic dilatation/aneurysm in patients with bicuspid aortic valve. NFIX, LMO4, DIP2C, C10orf41 (ZNF503-AS2), MED13L, TBX3, TBX5 are transcriptional regulators or modulators; NKD1 is a recognized inhibitor of the Wnt pathway. Our findings highlight the necessity of a rigorous approach to cohort design, which includes comprehensive phenotyping (encompassing aortic valve morphology) and underscore the importance of future single-cell investigations.

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