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

Aude-Marie Lepagnol-Bestel; Agnes Zvara; Gilles Maussion; Frédérique Quignon; Bedel Ngimbous; Nicolas Ramoz; Sandrine Imbeaud; Yann Loe-Mie; Karim Benihoud; Nicolas Agier; Paul Salin; Ana Cardona; Suonavy Khung-Savatovsky; Pekka Kallunki; Jean-Maurice Delabar; László Puskás; Hervé Delacroix; Lawrence Aggerbeck; Anne-Lise Delezoide; Olivier Delattre; Philip Gorwood; Jean-Marie Moalic; Michel Simonneau

doi:10.1093/hmg/ddp047

Journal articles

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

Aude-Marie Lepagnol-Bestel ¹ Agnes Zvara ² Gilles Maussion ¹ Frédérique Quignon ³ Bedel Ngimbous ¹ Nicolas Ramoz ¹ Sandrine Imbeaud ⁴ Yann Loe-Mie ¹ Karim Benihoud ⁵ Nicolas Agier ⁴ Paul Salin ⁶ Ana Cardona ⁷ Suonavy Khung-Savatovsky ⁸ Pekka Kallunki ⁹ Jean-Maurice Delabar ¹⁰ László Puskás ² Hervé Delacroix ⁴ Lawrence Aggerbeck ⁴ Anne-Lise Delezoide ⁸ Olivier Delattre ³ Philip Gorwood ¹ Jean-Marie Moalic ¹ Michel Simonneau ^{1, *}

* Corresponding author

1 Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs

2 Biological Research Center [Hungarian Academy of Sciences]

3 U830 - Unité de génétique et biologie des cancers

4 CGM - Centre de génétique moléculaire

5 VTG / UMR8121 - Vectorologie et transfert de gènes

6 Physio-pathologie des réseaux neuronaux du cycle veille-sommeil

7 Institut Pasteur [Paris]

8 Hôpital Robert Debré

9 Lundbeck SAS

10 EA_3508 - Modèles de dérégulation génique : trisomie 21 et hyperhomocystéinémie

UPD7 - Université Paris Diderot - Paris 7 : EA_3508, CNRS - Centre National de la Recherche Scientifique : EA3508

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.

Document type :

Journal articles

Domain :

Computer Science [cs] / Bioinformatics [q-bio.QM]

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https://hal-pasteur.archives-ouvertes.fr/pasteur-02875018
Contributor : Yann Loe-Mie <>
Submitted on : Friday, June 19, 2020 - 12:43:43 PM
Last modification on : Sunday, December 13, 2020 - 6:28:02 PM

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

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

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