Bioinformatic analyses of the role of m6A RNA methylation regulators in abdominal aortic aneurysm

Abstract

Background: N6-methyladenosine (m6A) is found in almost all nuclear RNAs of eukaryotes, playing an important and diverse role in many biological processes. Nonetheless, the roles of m6A regulators in abdominal aortic aneurysm (AAA) unknown. Therefore, there is a pressing need to identify m6A RNA methylation regulators in the diagnosis of AAA, determination of individualized risk, discovery of therapeutic targets, and improve understanding of pathogenesis.Methods: The GSE98278 dataset were obtained from the Gene Expression Omnibus (GEO) database to perform differential analysis of m6A-related regulators between elective stable abdominal aortic aneurysms (eAAA) and abdominal aortic aneurysm ruptured (rAAA). The random forest model was used to screen candidate m6A regulators to predict the risk of rAAA. The single sample gene set enrichment analysis (ssGSEA) method was then used to evaluate the abundance of 23 immune cells in AAA. The m6A RNA Methylation Quantification Kit was used to measure the total m6A levels of AAA and normal abdominal aorta. The terminal deoxynucleotidyl transferase mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay kit was used to detect the human aortic smooth muscle cells (HASMCs) apoptotic after RBM15 knockdown. Mechanically, RBM15 knockdown was found to reduce the expression of CASP3 in an m6A-dependent manner by Western blotting, RNA immunoprecipitation (RIP), and methylated RNA immunoprecipitation-quantitative polymerase chain reaction (MeRIP-RT-PCR).Results: RBM15, WTAP, ALKBH5, and IGFBP3 were highly expressed in rAAA. In contrast, RBM15B showed opposite results (P<0.05). The high m6A level in the rAAA compared with eAAA and normal abdominal aorta (P<0.05). The random forest model was used to screen 5 candidate m6A regulators to predict the risk of rAAA. Expression of the 5 m6A methylation regulators was validated in AAA samples (P<0.05). RBM15 knockdown inhibited the apoptosis of HASMCs. RBM15 knockdown reduced the expression of CASP3 in an m6A-dependent manner. A strong correlation between the five m6A methylation regulators and immune cell infiltration was identified.Conclusions: In summary, m6A regulators play nonnegligible roles in the occurrence of rAAA. Our investigation of m6A patterns may be able to guide future immunotherapy strategies for AAA.

Regulatory mechanism of RNA binding motif protein 15‐mediated N6 methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells

“…Thereafter, we focused on exploring the exact downstream mechanism of RBM15 in CRC cell functions. Accumulating studies have confirmed that RBM15‐catalyzed m 6 A modification participates in tumor pathogenesis and progression by regulating target gene expression and stability 29,31 . KLFs are a group of transcriptional regulators implicated in the development of certain malignancies, and some members of the KLF family are promising prognostic indicators for CRC 15 .…”

The abdominal aortic aneurysm-related disease model based on machine learning predicts immunity and m1A/m5C/m6A/m7G epigenetic regulation

“…Studies have also shown the expression pattern and functional significance of m6A-related genes in AAA (Zhang et al, 2021). m6A-related genes were found to play non-negligible roles in the occurrence of AAA ruptured (rAAA) (Fu et al, 2022). Besides, increased methylation levels of YTHDF3, FTO, and METTL14 were revealed to be associated with the progression of AAA (He et al, 2019b).…”

“…NSUN2 influences autotaxin expression and T cell recruitment to control aneurysm development (Miao et al, 2021). In AAA, Frontiers in Genetics frontiersin.org RBM15 knockdown decreased CASP3 expression in an m6Adependent way (Fu et al, 2022). In AAA, YBX1 was discovered to be a direct target of GAS5, and it also collaborated with GAS5 to control the downstream target p21 through a positive feedback loop (He et al, 2019a).…”

Comprehensive analysis of the expression of N6-methyladenosine RNA methylation regulators in pulmonary artery hypertension

“…The HNRNPA2B1, RBMX, and RBM15 levels were also observed to be significantly elevated in the PASMCs of IPAH patients ( Figure 8B ). RBM15 knockdown decreased the expression of CASP3 in an m6A-dependent manner and inhibited human aortic SMCs apoptosis ( Fu et al, 2022 ). RBM15 and RBMX facilitate the proliferation and invasiveness of tumors, such as hepatocellular carcinoma ( Song et al, 2020 ; Cai et al, 2021 ).…”