title: DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.
abstract: 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.
authors.affiliation: INSERM U675, IFR02, Faculté de Médecine Xavier Bichat, Université Paris Diderot-Paris 7, Paris, France.
authors.forename: Aude-Marie
authors.initials: AM
authors.lastname: Lepagnol-Bestel
authors.forename: Agnes
authors.initials: A
authors.lastname: Zvara
authors.forename: Gilles
authors.initials: G
authors.lastname: Maussion
authors.forename: Frédérique
authors.initials: F
authors.lastname: Quignon
authors.forename: Bedel
authors.initials: B
authors.lastname: Ngimbous
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ramoz
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.forename: Yann
authors.initials: Y
authors.lastname: Loe-Mie
authors.forename: Karim
authors.initials: K
authors.lastname: Benihoud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Agier
authors.forename: Paul A
authors.initials: PA
authors.lastname: Salin
authors.forename: Ana
authors.initials: A
authors.lastname: Cardona
authors.forename: Suonavy
authors.initials: S
authors.lastname: Khung-Savatovsky
authors.forename: Pekka
authors.initials: P
authors.lastname: Kallunki
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Delabar
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Puskas
authors.forename: Hervé
authors.initials: H
authors.lastname: Delacroix
authors.forename: Lawrence
authors.initials: L
authors.lastname: Aggerbeck
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Philip
authors.initials: P
authors.lastname: Gorwood
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Moalic
authors.forename: Michel
authors.initials: M
authors.lastname: Simonneau
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D003712:Dendrites / Q000502:physiology; D004314:Down Syndrome / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; D000097603:Dyrk Kinases; D000099229:RE1-Silencing Transcription Factor; C445179:SWI-SNF-B chromatin-remodeling complex