Abstract
This study investigated whether the promoter region of DNA methylation positively or negatively regulates tissue-specific genes (TSGs) and if it correlates with disease pathophysiology. We assessed tissue specificity metrics in five human tissues, using sequencing-based approaches, including 52 whole genome bisulfite sequencing (WGBS), 52 RNA-seq, and 144 chromatin immunoprecipitation sequencing (ChIP-seq) data. A correlation analysis was performed between the gene expression and DNA methylation levels of the TSG promoter region. The TSG enrichment analyses were conducted in the gene–disease association network (DisGeNET). The epigenomic association analyses of CpGs in enriched TSG promoters were performed using 1986 Infinium MethylationEPIC array data. A correlation analysis showed significant associations between the promoter methylation and 449 TSGs’ expression. A disease enrichment analysis showed that diabetes- and obesity-related diseases were high-ranked. In an epigenomic association analysis based on obesity, 62 CpGs showed statistical significance. Among them, three obesity-related CpGs were newly identified and replicated with statistical significance in independent data. In particular, a CpG (cg17075888 of PDK4), considered as potential therapeutic targets, were associated with complex diseases, including obesity and type 2 diabetes. The methylation changes in a substantial number of the TSG promoters showed a significant association with metabolic diseases. Collectively, our findings provided strong evidence of the relationship between tissue-specific patterns of epigenetic changes and metabolic diseases.
Highlights
The human body consists of more than 200 types of cells in various tissues that perform specific functions in different biological processes [1]
A pairwise correlation analysis was performed based on the transcripts per million (TPM) value
This study firstly suggests that a negative correlation between the hypo-methylated CpG on the PDK4 gene and its expression was highly associated with obesity
Summary
The human body consists of more than 200 types of cells in various tissues that perform specific functions in different biological processes [1]. The discovery of TSGs has broadened our understanding of the functions of various tissues [2,3,4], as well as their biological mechanisms [5], since the aberrant expression of TSGs may be implicated in various diseases [6]. Epigenetic events, including DNA methylation and histone modification, are key regulators of gene expression and phenotype [7]. Gene body methylation positively regulates gene expression [11,12,13]. Since the epigenetic level differs across human tissues, it is important to explore epigenetic factors to understand the mechanisms underlying TSGs
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