Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Genetics, National Research Institute for Family Planning, Health Department, Beijing, China.
PLoS One. 2022 May 11;17(5):e0268117. doi: 10.1371/journal.pone.0268117. eCollection 2022.
Diabetes mellitus causes an increased incidence of congenital heart malformations. However, the pathogenesis and potential epigenetic mechanism involved in this process are unclear. In this study, we used MethylRAD sequencing to compare changes in methylation levels in the genomic landscapes in the fetal heart in a rat model of hyperglycemia. Our results showed that methylation of CCGG/CCNGG sites were mostly enriched in intergenic regions, followed by intron, exon, upstream and the 5' and 3' untranslated regions. qRT-PCR results confirmed the MethylRAD sequencing findings, suggesting that abnormal CCGG/CCNGG methylation in the upstream region regulated gene expression. The differential methylation genes (DMGs) based on the CCGG and CCNGG sites in the upstream region were examined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Gene Ontology indicated that the CCGG-based DMGs involved in biological process and function were mainly related to transcription and co-SMAD binding. The CCNGG-based DMGs were mainly related to transcription and cytokine-mediated signaling pathways. Kyoto Encyclopedia of Genes and Genomes analysis indicated that CCGG-based DMGs were mainly involved in the Wnt signaling and TGF-β signaling pathways. CCNGG-based DMGs were involved in the TNF signaling and apoptosis pathways. These genes may play dominant roles in cardiomyocyte apoptosis and heart disease and require further study. These genes may also serve as potential molecular targets or diagnostic biomarkers for heart malformations under hyperglycemia.
糖尿病会增加先天性心脏畸形的发病率。然而，这一过程涉及的发病机制和潜在的表观遗传机制尚不清楚。在这项研究中，我们使用 MethylRAD 测序来比较高血糖大鼠模型胎儿心脏基因组景观中甲基化水平的变化。我们的结果表明，CCGG/CCNGG 位点的甲基化主要富集在基因间区，其次是内含子、外显子、上游区和 5'和 3'非翻译区。qRT-PCR 结果证实了 MethylRAD 测序的发现，表明上游区异常的 CCGG/CCNGG 甲基化调节基因表达。通过基因本体论和京都基因与基因组百科全书分析，对上游区基于 CCGG 和 CCNGG 位点的差异甲基化基因（DMGs）进行了检查。基因本体论表明，基于 CCGG 的 DMGs 在生物学过程和功能方面的参与主要与转录和共同 SMAD 结合有关。基于 CCNGG 的 DMGs 主要与转录和细胞因子介导的信号通路有关。京都基因与基因组百科全书分析表明，基于 CCGG 的 DMGs 主要参与 Wnt 信号和 TGF-β 信号通路。基于 CCNGG 的 DMGs 参与 TNF 信号和细胞凋亡途径。这些基因可能在心肌细胞凋亡和心脏病中发挥主导作用，需要进一步研究。这些基因也可能作为高血糖引起的心脏畸形的潜在分子靶点或诊断生物标志物。
