title: High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies.
abstract: Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
authors.affiliation: Inserm U613, Brest, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Quillé
authors.forename: Solenne
authors.initials: S
authors.lastname: Carat
authors.forename: Sylvia
authors.initials: S
authors.lastname: Quéméner-Redon
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirchaud
authors.forename: Daniel
authors.initials: D
authors.lastname: Baron
authors.forename: Caroline
authors.initials: C
authors.lastname: Benech
authors.forename: Jeanne
authors.initials: J
authors.lastname: Guihot
authors.forename: Morgane
authors.initials: M
authors.lastname: Placet
authors.forename: Olivier
authors.initials: O
authors.lastname: Mignen
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Rémi
authors.initials: R
authors.lastname: Houlgatte
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Friocourt
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000089662:Doublecortin Protein; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C469265:ARX protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D014157:Transcription Factors