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Transcriptome and N6-Methyladenosine RNA Methylome Analyses in Aortic Dissection and Normal Human Aorta.

ABSTRACT: Objective: To investigate the N6-methyladenosine (m6A) modification and the expressions of the m6A regulatory genes in the acute aortic dissection (AD). Methods: MeRIP-seq and RNA-seq experiments of aortic media tissue samples obtained from AD (n = 4) and Controls (n = 4) were conducted. m6A methylation quantification was used to measure the total mRNA m6A level. The five m6A regulators mRNA expressions were analyzed by quantitative polymerase chain reaction (qPCR). Western blot analyses and immunofluorescence staining were used to detect the difference of METTL14 protein expression in the aortas of AD and Normal. Results: Among AD patients, we detected significantly elevated levels of m6A in total RNA. Compared with the normal group, the up methylated coding genes of AD were primarily enriched in the processes associated with extracellular fibril organization, while the genes with down methylation were enriched in the processes associated with cell death regulation. Furthermore, many differentially methylated m6A sites (DMMSs) coding proteins were mainly annotated during the extracellular matrix and inflammatory responses. Conclusions: These findings indicate that differential m6A methylation and m6A regulatory genes, including MTEEL14 and FTO, may act on functional genes through RNA modification, thereby regulating the pathogenesis of aortic dissection.

SUBMITTER: Zhou X

PROVIDER: S-EPMC8193080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.

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Transcriptome and N6-Methyladenosine RNA Methylome Analyses in Aortic Dissection and Normal Human Aorta.

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