Regulation of DNA methylation and 2-OG/TET signaling by choline alleviated cardiac hypertrophy in spontaneously hypertensive rats

DNA methylation is a well-defined epigenetic modification that regulates gene transcription. However, the role of DNA methylation in the cardiac hypertrophy seen in hypertension is unclear. This study was performed to investigate genome-wide DNA methylation profiles in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKY), and the cardioprotective effect of choline. Eight-week-old male SHRs received intraperitoneal injections of choline (8 mg/kg/day) for 8 weeks. SHRs showed aberrant methylation distribution on chromosomes and genome regions, with decreased methylation levels at CHG and CHH sites. A total of 91,559 differentially methylated regions (DMRs) were detected between SHRs and WKY rats, of which 28,197 were demethylated and 63,362 were methylated. Choline treatment partly restored the DMRs in SHRs, which were related to 131 genes. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis of DMRs suggested that choline partly reversed the dysfunctions of biological processes, cellular components and molecular functions in SHRs. Moreover, the inhibition of 2-oxoglutarate accumulation by choline, thereby inhibiting excessive activation of ten-eleven translocation methylcytosine dioxygenase enzymes, may correlate with the beneficial effects of choline on methylation levels, cardiac hypertrophy and cardiac function of SHRs, as indicated by decreased heart rate and blood pressure, and increased ejection fraction and fractional shortening. This study provides the first genome-wide DNA methylation profile of the hypertrophic myocardium of SHRs and suggests a novel role for this epigenetic modification in hypertension. Choline treatment may represent a promising approach for modification of DNA methylation and optimization of the epigenetic profile for antihypertensive therapy.