The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes
Shawn McClelland,
Gary P Brennan,
Celine Dubé,
Seeta Rajpara,
Shruti Iyer,
Cristina Richichi,
Christophe Bernard,
Tallie Z Baram
Affiliations
Shawn McClelland
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
Gary P Brennan
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
Celine Dubé
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
Seeta Rajpara
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
Shruti Iyer
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
Cristina Richichi
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
Christophe Bernard
Laboratoire Epilepsie et Cognition, Institut National de la Santé et de la Recherche Médicale, Marseille, France
Tallie Z Baram
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
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.
