Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.
Dr. B R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
Sci Rep. 2018 Dec 19;8(1):17976. doi: 10.1038/s41598-018-35892-5.
Focal cortical dysplasia (FCD) is one of the most common pathologies associated with drug-resistant epilepsy (DRE). The pharmacological targets remain obscured, as the molecular mechanisms underlying FCD are unclear. Implications of epigenetically modulated aberrant gene expression in disease progression are reported in various DRE pathologies except FCD. Here we performed genome-wide CpG-DNA methylation profiling by methylated DNA immunoprecipitation (MeDIP) microarray and RNA sequencing (RNAseq) on cortical tissues resected from FCD type II patients. A total of 19088 sites showed altered DNA methylation in all the CpG islands. Of these, 5725 sites were present in the promoter regions, of which 176 genes showed an inverse correlation between methylation and gene expression. Many of these 176 genes were found to belong to a cohesive network of physically interacting proteins linked to several cellular functions. Pathway analysis revealed significant enrichment of receptor tyrosine kinases (RTK), EGFR, PDGFRA, NTRK3, and mTOR signalling pathways. This is the first study that investigates the epigenetic signature associated with FCD type II pathology. The candidate genes and pathways identified in this study may play a crucial role in the regulation of the pathogenic mechanisms of epileptogenesis associated with FCD type II pathologies.
局灶性皮质发育不良（FCD）是与耐药性癫痫（DRE）相关的最常见病理之一。由于 FCD 的分子机制尚不清楚，其药理学靶点仍然不清楚。除了 FCD 之外，在各种 DRE 病理中都有报道表明表观遗传调节的异常基因表达在疾病进展中的作用。在这里，我们对来自 FCD Ⅱ型患者的皮质组织进行了全基因组 CpG-DNA 甲基化谱分析，通过甲基化 DNA 免疫沉淀（MeDIP）微阵列和 RNA 测序（RNAseq）。共有 19088 个位点在所有 CpG 岛显示出改变的 DNA 甲基化。其中，5725 个位点位于启动子区域，其中 176 个基因的甲基化与基因表达呈负相关。这些基因中的许多都属于物理相互作用的蛋白质的凝聚网络，与多种细胞功能有关。通路分析显示，受体酪氨酸激酶（RTK）、EGFR、PDGFRA、NTRK3 和 mTOR 信号通路显著富集。这是第一项研究 FCD Ⅱ型病理相关的表观遗传特征的研究。本研究中鉴定的候选基因和途径可能在与 FCD Ⅱ型病理相关的致痫机制的调节中起关键作用。
