title: The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes.
abstract: The mechanisms generating epileptic neuronal networks following insults such as severe seizures are unknown. We have previously shown that interfering with the function of the neuron-restrictive silencer factor (NRSF/REST), an important transcription factor that influences neuronal phenotype, attenuated development of this disorder. In this study, we found that epilepsy-provoking seizures increased the low NRSF levels in mature hippocampus several fold yet surprisingly, provoked repression of only a subset (∼10%) of potential NRSF target genes. Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked. Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels. Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function. Thus, dynamic, selective regulation of NRSF target genes may play a role in influencing neuronal properties in pathological and physiological contexts.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: McClelland
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Celine
authors.initials: C
authors.lastname: Dubé
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Seeta
authors.initials: S
authors.lastname: Rajpara
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Richichi
authors.affiliation: Laboratoire Epilepsie et Cognition, Institut National de la Santé et de la Recherche Médicale, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, United States Department of Pediatrics, University of California, Irvine, Irvine, United States Department of Neurology, University of California, Irvine, Irvine, United States tallie@uci.edu.
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D000818:Animals; D001692:Biological Transport; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008867:Microtomy; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002843:Chromatin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: epilepsy; gene set enrichment analysis; neuron-restrictive silencing factor