Integrated Analysis of Tissue-Specific Promoter Methylation and Gene Expression Profile in Complex Diseases

• Published in: International journal of molecular sciences 2020-07, Vol.21 (14), p.5056
• Main Authors: Lee, Kibaick, Moon, Sanghoon, Park, Mi-Jin, Koh, In-Uk, Choi, Nak-Hyeon, Yu, Ho-Yeong, Kim, Young Jin, Kong, Jinhwa, Kang, Hee Gyung, Kim, Song Cheol, Kim, Bong-Jo
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Association analysis; Binding sites; Bisulfite; Chromatin; Correlation analysis; CpG Islands; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Disease; DNA; DNA Methylation; Enrichment; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Regulatory Networks; Genome, Human; Genomes; Human tissues; Humans; Immunoprecipitation; Insulin resistance; Metabolic disorders; Metabolism; Obesity; Obesity - genetics; Organ Specificity - genetics; Pathophysiology; Process controls; Promoter Regions, Genetic; Promoters; Signal transduction; Statistical significance; Statistics; Studies; Therapeutic applications; tissue-specific expression; Transcriptome; type 2 diabetes; Whole Genome Sequencing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21145056

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 ), 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.