A regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX (Abstract/Poster in atti di convegno)

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  • A regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX (Abstract/Poster in atti di convegno) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Alternative label
  • Poeta L, Fusco F, Shoubridge C, Manganelli G, Filosa S, Padula A, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV and Miano MG (2013)
    A regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX
    in European Society of Human Genetics 2013, Paris, France, June 8-11-2013
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Poeta L, Fusco F, Shoubridge C, Manganelli G, Filosa S, Padula A, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV and Miano MG (literal)
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  • Poster (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Institute of Genetics and Biophysics \"Adriano Buzzati Traverso\", CNR, Naples 80131, Italy University of Basilicata, Potenza 85100, Italy Department of Paediatrics, University of Adelaide, Australia, South Australia 5006, Australia Department of Genetics and Molecular Pathology, SA, Pathology, Adelaide, Australia IRCCS, Neuromed, Pozzilli 86077, Italy Universitè de Nice-Sophia Antipolis, FR-06108, Nice, France Inserm U1091, IBV, Diabetes Genetics Team, FR-06108 Nice, France (literal)
Titolo
  • A regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX (literal)
Abstract
  • Polyalanine expansion mutations of Aristaless-related homeobox gene (ARX) cause a spectrum of X-chromosome phenotypes with Intellectual Disabilily (ID) and various forms of malignant paediatric epilepsy. We have established that ARX regulates and binds a CNE element in the 5' region of the lysine (K)-specific demethylase 5C (KDM5C), a known XLID gene involved in chromatin remodeling and neuronal maturation. By in vitro studies, we have analyzed five Polyalanine mutants establishing a decreased trans-activating activity and a reduced, but not abolished, binding to the KDM5C regulatory region. By quantitative RT-PCR, we have showed in murine Arx-KO ES cells and neurospheres a dramatic downregulation of the Kdm5C mRNA levels that leads to a decrease of the KDM5C protein. In Arx KO GABA-oriented model, which presents severe abnormalities in dendrite formation and GABAergic maturation, we have found a KDM5C reduction in coupling with a global increase of H3K4me3 signalling, potentially due to a compromised KDM5C activity. Since H3K4me3 is the hallmark of open chromatin, ARX-dependent KDM5C defects could compromise cyclical rounds of methylation-demethylation and consequently the chromatin remodelling. Starting from these data, we are now able to break up a unique ARX-dependent epigenetic road involved in epileptogenesis, suggesting that the molecular pathogenesis of ARX Polyalanine mutations may be in part caused by aberrant histone demethylation as a result of KDM5C defect. As chromatin modifications are reversible, it is possible that epigenetic drugs could compensate KDM5C-H3K4me3 deregulation opening further studies to cure or ameliorate ARX Polyalanine-related epilepsy. (literal)
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