Integrative analysis of methylome and transcriptome variation of identified cardiac disease-specific genes in human cardiomyocytes after PM2.5 exposure

PM2.5 exposure is strongly linked to cardiac disease. Subtle epigenetic or transcriptional alterations induced by PM2.5 might contribute to pathogenesis and disease susceptibility of cardiac disease. It is still a major challenge to identify biological targets in human genetics. Human cardiomyocytes AC16 was chosen as cell model. Epigenetic effect of PM2.5 in AC16 was analyzed using Illumina HumanMethylation 450 K BeadChip. Meanwhile the transcriptomic profiling was performed by Affymetrix® microarray. PM2.5 induced genome wide variation of DNA methylation pattern, including differentially methylated CpGs in promoter region. Then gene ontology analysis demonstrated differentially methylated genes were significantly clustered in pathways in regulation of apoptotic process, cell death and metabolic pathways, or associated with ion binding and shuttling. Correlation of the methylome and transcriptome revealed a clear bias toward transcriptional suppression by hypermethylation or activation by hypomethylation. Identified 386 genes which exhibited both differential methylation and expression were functionally associated with pathways including cardiovascular system development, regulation of blood vessel size, vasculature development, p53 pathway, AC-modulating/inhibiting GPCRs pathway and cellular response to metal ion/inorganic substance. Disease ontology demonstrated their prominent role in cardiac diseases and identified 14 cardiac-specific genes (ANK2, AQP1 et al.). PPI network analysis revealed 6 novel genes (POLR2I, LEP, BRIX1, ADCY6, INSL3, RARS). Those genes were then verified by qRT-PCR. Thus, in AC16, PM2.5 alters the methylome and transcriptome of genes might be relevant for PM2.5-/heart-associated diseases. Result gives additional insight in PM2.5 relative cardiac diseases/associated genes and the potential mechanisms that contribute to PM2.5 related cardiac disease.