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.

Department of Medicine Campus Bio Medico University of Rome Rome Italy

Department of Pathology 2nd Faculty of Medicine Charles University Motol University Hospital Prague Czech Republic

Department of Pathology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology 2nd Faculty of Medicine Charles University Motol University Hospital Prague Czech Republic

Department of Pediatric Neurology Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatrics Medical University Vienna Vienna Austria

European Center for Brain Research IRCCS Santa Lucia Foundation Via del Fosso di Fiorano 64 65 00143 Rome Italy

Institute of Neurology Medical University Vienna Vienna Austria

Stichting Epilepsie Instellingen Nederland Heemstede The Netherlands

Swammerdam Institute for Life Sciences Center for Neuroscience University of Amsterdam Amsterdam The Netherlands

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