Promoter-Specific Hypomethylation Correlates with IL-1β Overexpression in Tuberous Sclerosis Complex (TSC).
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.
European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy.
A
A
Fuso
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
A M
AM
Iyer
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
J
J
van Scheppingen
European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy.|Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
M
M
Maccarrone
Department of Pediatrics, Medical University Vienna, Vienna, Austria.
T
T
Scholl
Institute of Neurology, Medical University Vienna, Vienna, Austria.
J A
JA
Hainfellner
Department of Pediatrics, Medical University Vienna, Vienna, Austria.
M
M
Feucht
Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
F E
FE
Jansen
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
W G
WG
Spliet
Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic.
P
P
Krsek
Department of Pathology, 2nd Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic.
J
J
Zamecnik
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Department of Pediatrics, Medical University Vienna, Vienna, Austria.
A
A
Mühlebner
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.|Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.|Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands. e.aronica@amc.uva.nl.
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Aronica
D000293:Adolescent; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D053583:Interleukin-1beta
Cortical tuber; Epigenetic regulation; Inflammation; Interleukin-1β; Tuberous sclerosis complex