Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction
Open Access
- 5 March 2021
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Cardiovascular Medicine
Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease, in which its pathogenesis is very complex and far from defined. Here, we explored the N6-methyladenosine (m6A) RNA methylation alteration in patients with HFpEF and mouse model of HFpEF. Methods: In this case–control study, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood samples obtained from 16 HFpEF patients and 24 healthy controls. The change of m6A regulators was detected by quantitative real-time PCR (RT-PCR). A “two-hit” mouse model of HFpEF was induced by a high-fat diet and drinking water with 0.5 g/L of Nω-nitro-l-arginine methyl ester (L-NAME). MeRIP-seq was used to map transcriptome-wide m6A in control mice and HFpEF mice, and the gene expression was high-throughput detected by RNA-seq. Results: The expression of m6A writers METTL3, METTL4, and KIAA1429; m6A eraser FTO; and reader YTHDF2 was up-regulated in HFpEF patients, compared with health controls. Furthermore, the expression of FTO was also elevated in HFpEF mice. A total of 661 m6A peaks were significantly changed by MeRIP-seq. Gene Ontology (GO) analysis revealed that protein folding, ubiquitin-dependent ERAD pathway, and positive regulation of RNA polymerase II were the three most significantly altered biological processes in HFpEF. The pathways including proteasome, protein processing in the endoplasmic reticulum, and PI3K-Akt signaling pathway were significantly changed in HFpEF by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Conclusions: The expression pattern of m6A regulators and m6A landscape is changed in HFpEF. This uncovers a new transcription-independent mechanism of translation regulation. Therefore, our data suggest that the modulation of epitranscriptomic processes, such as m6A methylation, might be an interesting target for therapeutic interventions.Keywords
This publication has 43 references indexed in Scilit:
- 5′ UTR m6A Promotes Cap-Independent TranslationCell, 2015
- Dynamic m6A mRNA methylation directs translational control of heat shock responseNature, 2015
- N6-methyladenosine Modulates Messenger RNA Translation EfficiencyCell, 2015
- m 6 A mRNA methylation facilitates resolution of naïve pluripotency toward differentiationScience, 2015
- Chromatin methylation and cardiovascular agingJournal of Molecular and Cellular Cardiology, 2015
- FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesisCell Research, 2014
- Heart Failure With Preserved Ejection FractionCirculation Research, 2014
- Diabetes Mellitus and Myocardial Mitochondrial Dysfunction: Bench to BedsideHeart Failure Clinics, 2012
- Topology of the human and mouse m6A RNA methylomes revealed by m6A-seqNature, 2012
- A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failureProceedings of the National Academy of Sciences of the United States of America, 2006