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Changes in N6-Methyladenosine Modification Modulate Diabetic Cardiomyopathy by Reducing Myocardial Fibrosis and Myocyte Hypertrophy.

ABSTRACT: In this study, we aimed to systematically profile global RNA N6-methyladenosine (m⁶A) modification patterns in a mouse model of diabetic cardiomyopathy (DCM). Patterns of m⁶A in DCM and normal hearts were analyzed via m⁶A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). m⁶A-related mRNAs were validated by quantitative real-time PCR analysis of input and m⁶A immunoprecipitated RNA samples from DCM and normal hearts. A total of 973 new m⁶A peaks were detected in DCM samples and 984 differentially methylated sites were selected for further study, including 295 hypermethylated and 689 hypomethylated m⁶A sites (fold change (FC) > 1.5, P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analyses indicated that unique m⁶A-modified transcripts in DCM were closely linked to cardiac fibrosis, myocardial hypertrophy, and myocardial energy metabolism. Total m⁶A levels were higher in DCM, while levels of the fat mass and obesity-associated (FTO) protein were downregulated. Overexpression of FTO in DCM model mice improved cardiac function by reducing myocardial fibrosis and myocyte hypertrophy. Overall, m⁶A modification patterns were altered in DCM, and modification of epitranscriptomic processes, such as m⁶A, is a potentially interesting therapeutic approach.

SUBMITTER: Ju W

PROVIDER: S-EPMC8334868 | biostudies-literature |

REPOSITORIES: biostudies-literature

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