The m6A demethylase ALKBH5 is a novel epigenetic regulator of aortic valve calcification

Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

Calcific aortic valve disease (CAVD) is a common heart with significant clinical consequences. The mechanisms that drive the pathogenesis of CAVD remain to be fully elucidated. N6-methyladenosine (m6A), most prevalent RNA epigenetic regulator, has recently been implicated in cardiovascular disease, but its role yet investigated. In this study, we investigated potential function m6A modification CAVD. Using samples from patients combination human interstitial cell (hVIC) calcification model, screened expression modulators and discovered ALKBH5 alkB homolog 5, demethylase (ALKBH5), key demethylase, was significantly down-regulated calcified hVICs valves. Consistently, increased levels were seen hVICs, treated 3-deazaadenosine (DAA), an inhibitor modification, reduced hVIC osteogenic differentiation calcification. addition, showed silencing global levels, accelerated calcification, whereas overexpression resulted opposite effect. We demonstrated directly modulate TGFBR2 mRNA stability, leading altered SMAD2 signaling hVICs. further inhibition or knockdown attenuated knockdown-induced reader protein YTH binding F1 (YTHDF1) upregulated during process Intriguingly, revealed silencing-induced abolished after YTHDF1. These data suggest YTHDF1 This study through TGFBR2/SMAD2 pathway via direct TGFBR2. .

Language: Английский

Detecting the Tumor Prognostic Factors From the YTH Domain Family Through Integrative Pan-Cancer Analysis

Cancer Informatics, Journal Year: 2024, Volume and Issue: 23

Published: Jan. 1, 2024

Objectives: Emerging evidence suggests that N6-methyladenosine (m 6 A) methylation plays a critical role in cancers through various mechanisms. This work aims to reveal the essential of m A “readers” regulation cancer prognosis at pan-cancer level. Methods: Herein, we focused on one special protein family methylation, YT521-B homology (YTH) domain genes, which were observed be frequently dysregulated tumor tissues and closely associated with prognosis. Then, comprehensive analysis modulation was conducted by integrating RNA sequencing (RNAseq) datasets YTH genes clinical information Results: significantly differentially expressed most cancers, particularly increased Gastrointestinal decreased Endocrine Urologic cancers. In addition, they overall survival (OS) disease-specific (DSS) extent, especially lower grade glioma (LGG), thyroid (THCA), liver hepatocellular carcinoma (LIHC) kidney clear cell (KIRC), so some “writers” (METLL3, METLL14, WTAP) “erasers” (FTO, ALKBH5). Further illustrated specifically YTHScore constructed combining 5 as well RWEScore calculated from “readers”-“writers”-“erasers” could dramatically distinguish 4 representative As expected, presented an equally comparable prognostic classification RWEScore. Finally, immune signatures characteristics implied that, activity innate immune, diagnostic age, stage, Tumor-Node-Metastasis (TNM) stage types, might play specific roles modulating Conclusions: The study demonstrated had potential predict prognosis, equal ability compared RWEScore, thus providing insights into biomarkers therapeutic targets

Language: Английский

Non-coding RNAs mediating the regulation of genes and signaling pathways in aortic valve calcification

Gene, Journal Year: 2024, Volume and Issue: unknown, P. 149117 - 149117

Published: Nov. 1, 2024

Language: Английский