Fuso A, Iyer A M, van Scheppingen J, Maccarrone M, Scholl T, Hainfellner J A, Feucht M, Jansen F E, Spliet W G, Krsek P, Zamecnik J, Mühlebner A, Aronica E
European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy.
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
J Mol Neurosci. 2016 Aug;59(4):464-70. doi: 10.1007/s12031-016-0750-7. Epub 2016 Apr 28.
In tuberous sclerosis complex (TSC), overexpression of numerous genes associated with inflammation has been observed. Among different proinflammatory cytokines, interleukin-1β (IL-1β) has been shown to be significantly involved in epileptogenesis and maintenance of seizures. Recent evidence indicates that IL-1β gene expression can be regulated by DNA methylation of its promoter. In the present study, we hypothesized that hypomethylation in the promoter region of the IL-1β gene may underlie its overexpression observed in TSC brain tissue. Bisulfite sequencing was used to study the methylation status of the promoter region of the IL-1β gene in TSC and control samples. We identified hypomethylation in the promoter region of the IL-1β gene in TSC samples. IL-1β is overexpressed in tubers, and gene expression is correlated with promoter hypomethylation at CpG and non-CpG sites. Our results provide the first evidence of epigenetic modulation of the IL-1β signaling in TSC. Thus, strategies that target epigenetic alterations could offer new therapeutic avenues to control the persistent activation of interleukin-1β-mediated inflammatory signaling in TSC brain.
在结节性硬化症（TSC）中，已观察到许多与炎症相关的基因过表达。在不同的促炎细胞因子中，白细胞介素-1β（IL-1β）已被证明在癫痫发生和癫痫维持中起重要作用。最近的证据表明，IL-1β基因表达可受其启动子DNA甲基化调控。在本研究中，我们假设IL-1β基因启动子区域的低甲基化可能是TSC脑组织中观察到的其过表达的基础。采用亚硫酸氢盐测序法研究TSC和对照样本中IL-1β基因启动子区域的甲基化状态。我们在TSC样本中鉴定出IL-1β基因启动子区域低甲基化。IL-1β在结节中过表达，且基因表达与CpG和非CpG位点的启动子低甲基化相关。我们的结果为TSC中IL-1β信号通路的表观遗传调控提供了首个证据。因此，针对表观遗传改变的策略可能为控制TSC脑内白细胞介素-1β介导的炎症信号通路的持续激活提供新的治疗途径。
