DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome

Autor: Suonavy Khung-Savatovsky, Sandrine Imbeaud, Karim Benihoud, Jean Marie Moalic, Anne Lise Delezoide, László G. Puskás, Bedel Ngimbous, Pekka Kallunki, Nicolas Ramoz, Gilles Maussion, Ana Cardona, Paul A. Salin, Hervé Delacroix, Philip Gorwood, Michel Simonneau, Yann Loe-Mie, Lawrence Aggerbeck, Aude-Marie Lepagnol-Bestel, Nicolas Agier, Jean-Maurice Delabar, Olivier Delattre, Ágnes Zvara, Frédérique Quignon
Přispěvatelé: Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biological Research Center [Hungarian Academy of Sciences], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Hôpital Robert Debré, Lundbeck SAS, Modèles de dérégulation génique : trisomie 21 et hyperhomocystéinémie (EA_3508), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was supported by INSERM, the CNRS, Fondation Jérôme Lejeune, Association Française du Syndrome de Rett, the Ile de France Region, the Fondation de France, the University of Paris South (XI), Sanofi-Aventis ANR06-neuro FRAXAmRNP and the Hungarian National Office for Research and Technology grant (NKTH, RET-08/2004), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]
Rok vydání: 2009
Předmět:
Zdroj: Human Molecular Genetics
Human Molecular Genetics, 2009, 18 (8), pp.1405-1414. ⟨10.1093/hmg/ddp047⟩
Human Molecular Genetics, Oxford University Press (OUP), 2009, 18 (8), pp.1405-1414. ⟨10.1093/hmg/ddp047⟩
ISSN: 1460-2083
0964-6906
DOI: 10.1093/hmg/ddp047
Popis: International audience; The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.
Databáze: OpenAIRE
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