AUTHOR=Shi Hangchuan , Chen Si , Meng Fanju W. , Ossip Deborah J. , Yan Chen , Li Dongmei 

TITLE=Epigenome-wide DNA methylation profiling in comparison between pathological and physiological hypertrophy of human cardiomyocytes

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1264382

DOI=10.3389/fgene.2023.1264382

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Physiological and pathological stimuli result in distinct forms of cardiac hypertrophy, but the molecular regulation comparing the two, especially at the DNA methylation level, is not well understood.</p><p><bold>Methods:</bold> We conducted an <italic>in vitro</italic> study using human cardiomyocytes exposed to angiotensin II (AngII) and insulin-like growth factor 1 (IGF-1) to mimic pathologically and physiologically hypertrophic heart models, respectively. Whole genome DNA methylation patterns were profiled by the Infinium human MethylationEPIC platform with &gt;850 K DNA methylation loci. Two external datasets were used for comparisons and qRT-PCR was performed for examining expression of associated genes of those identified DNA methylation loci.</p><p><bold>Results:</bold> We detected 194 loci that are significantly differentially methylated after AngII treatment, and 206 significant loci after IGF-1 treatment. Mapping the significant loci to genes, we identified 158 genes corresponding to AngII treatment and 175 genes to IGF-1 treatment. Using the gene-set enrichment analysis, the PI3K-Akt signaling pathway was identified to be significantly enriched for both AngII and IGF-1 treatment. The Hippo signaling pathway was enriched after IGF-1 treatment, but not for AngII treatment. <italic>CDK6</italic> and <italic>RPTOR</italic> are components of the PI3K-Akt pathway but have different DNA methylation patterns in response to AngII and IGF-1. qRT-PCR confirmed the different gene expressions of <italic>CDK6</italic> and <italic>PRTOR</italic>.</p><p><bold>Conclusion:</bold> Our study is pioneering in profiling epigenome DNA methylation changes in adult human cardiomyocytes under distinct stress conditions: pathological (AngII) and physiological (IGF-1). The identified DNA methylation loci, genes, and pathways might have the potential to distinguish between pathological and physiological cardiac hypertrophy.</p>