Ko Yi-An, Mohtat Davoud, Suzuki Masako, Park Ae Seo Deok, Izquierdo Maria Concepcion, Han Sang Youb, Kang Hyun Mi, Si Han, Hostetter Thomas, Pullman James M, Fazzari Melissa, Verma Amit, Zheng Deyou, Greally John M, Susztak Katalin
Genome Biol. 2013;14(10):R108. doi: 10.1186/gb-2013-14-10-r108.
One in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. Epigenetic information represents a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences.
We identify differentially methylated regions and validate these in a large replication dataset. The differentially methylated regions are rarely observed on promoters, but mostly overlap with putative enhancer regions, and they are enriched in consensus binding sequences for important renal transcription factors. This indicates their importance in gene expression regulation. A core set of genes that are known to be related to kidney fibrosis, including genes encoding collagens, show cytosine methylation changes correlating with downstream transcript levels.
Our report raises the possibility that epigenetic dysregulation plays a role in chronic kidney disease development via influencing core pro-fibrotic pathways and can aid the development of novel biomarkers and future therapeutics.
每十一人中就有一人受慢性肾病影响，该病症以肾纤维化和肾功能进行性丧失为特征。流行病学研究表明，不良的宫内和产后环境在慢性肾病发展过程中具有长期作用。表观遗传信息是介导这种编程效应的一个合理载体。在此，我们证明从患者获取的健康和慢性肾病肾小管样本的全基因组胞嘧啶甲基化模式存在显著差异。
我们鉴定出差异甲基化区域，并在一个大型复制数据集中对其进行验证。差异甲基化区域很少在启动子上观察到，但大多与假定的增强子区域重叠，并且它们富含重要肾转录因子的共有结合序列。这表明它们在基因表达调控中的重要性。一组已知与肾纤维化相关的核心基因，包括编码胶原蛋白的基因，显示出胞嘧啶甲基化变化与下游转录水平相关。
我们的报告提出了一种可能性，即表观遗传失调通过影响核心促纤维化途径在慢性肾病发展中起作用，并且有助于新型生物标志物的开发和未来治疗方法的研发。
