Department of Nephrology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Cell Physiol. 2018 Oct;233(10):7139-7147. doi: 10.1002/jcp.26638. Epub 2018 May 8.
Diabetic nephropathy (DN) is one of the most common and serious complication in diabetes patients. However, the evidences of gene regulation mechanism and epigenetic modification with DN remain unclear. Therefore, it is necessary to search regulating genes for early diagnosis on DN. We identified tissue specific genes through mining the gene expression omnibus (GEO) public database, enriched function by gene ontology (GO), and kyoto encyclopedia of genes and genomes (KEGG) analysis, and further compared tissue-specific network. Meanwhile, combining with differentially methylated sites, we explored the association epigenetic modification with the pathogenesis of DN. Glomeruli (Glom) may be the main tissue of signal recognition and tubulointerstitium (Tub) is mainly associated with energy metabolism in the occurrence of DN. By comparing tissue-specific networks between Glom and Tub, we screened 319 genes, which played an important role in multiple tissue on kidney. Among them, ANXA2, UBE2L6, MME, IQGAP, SLC7A7, and PLG played a key role in regulating the incidence of DN. Besides, we also identified 1 up-regulated gene (PIK3C2B) and 39 down-regulated genes (POLR2G, DDB1, and ZNF230, etc.) in the methylated data of Glom specific genes. In the Tub specific expressed genes, we identified two hypo-methylated genes (PPARA and GLS). Tub mainly caused abnormal energy metabolism, and Glom caused the changes in cell connections and histone modification. By analyzing differentially methylated sites and tissue-specific expressed genes, we found the change of methylated status about the core regulating genes may be a potential factor in the pathogenesis of DN.
糖尿病肾病（DN）是糖尿病患者最常见和最严重的并发症之一。然而，DN 的基因调控机制和表观遗传修饰的证据尚不清楚。因此，有必要寻找调节基因，以便对 DN 进行早期诊断。我们通过挖掘基因表达综合数据库（GEO）公共数据库来识别组织特异性基因，通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析进行功能富集，并进一步比较组织特异性网络。同时，结合差异甲基化位点，探讨了表观遗传修饰与 DN 发病机制的关系。肾小球（Glom）可能是信号识别的主要组织，而小管间质（Tub）主要与 DN 发生时的能量代谢有关。通过比较 Glom 和 Tub 之间的组织特异性网络，我们筛选出 319 个基因，这些基因在肾脏的多个组织中发挥重要作用。其中，ANXA2、UBE2L6、MME、IQGAP、SLC7A7 和 PLG 在调节 DN 的发生中起关键作用。此外，我们还在 Glom 特异性基因的甲基化数据中鉴定出 1 个上调基因（PIK3C2B）和 39 个下调基因（POLR2G、DDB1 和 ZNF230 等）。在 Tub 特异性表达的基因中，我们鉴定出 2 个低甲基化基因（PPARA 和 GLS）。Tub 主要导致异常能量代谢，而 Glom 导致细胞连接和组蛋白修饰的变化。通过分析差异甲基化位点和组织特异性表达基因，我们发现核心调节基因的甲基化状态的变化可能是 DN 发病机制的一个潜在因素。
