Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do 28519, Korea.
Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea.
Int J Mol Sci. 2020 Jul 17;21(14):5056. 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.
本研究旨在探讨 DNA 甲基化启动子区域是正向还是负向调控组织特异性基因（TSG），以及它是否与疾病病理生理学相关。我们评估了五个人体组织的组织特异性指标，采用基于测序的方法，包括 52 个全基因组亚硫酸氢盐测序（WGBS）、52 个 RNA-seq 和 144 个染色质免疫沉淀测序（ChIP-seq）数据。我们对 TSG 启动子区域的基因表达和 DNA 甲基化水平进行了相关性分析。在基因-疾病关联网络（DisGeNET）中进行了 TSG 富集分析。在 1986 个 Infinium MethylationEPIC 阵列数据中，对富含 TSG 启动子的 CpG 进行了表观基因组关联分析。相关性分析显示，启动子甲基化与 449 个 TSG 的表达之间存在显著相关性。疾病富集分析显示，与糖尿病和肥胖相关的疾病排名较高。在基于肥胖的表观基因组关联分析中，有 62 个 CpG 显示出统计学意义。其中，有三个与肥胖相关的 CpG（cg17075888 于 ）是新发现的，在独立数据中具有统计学意义的复制。特别是，一个 CpG（cg17075888 于 ）被认为是潜在的治疗靶点，与肥胖和 2 型糖尿病等复杂疾病有关。大量 TSG 启动子的甲基化变化与代谢疾病有显著关联。总之，我们的研究结果为组织特异性表观遗传变化与代谢疾病之间的关系提供了强有力的证据。
