High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies.
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3178625?pdf=render |
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| author | Marie-Lise Quillé Solenne Carat Sylvia Quéméner-Redon Edouard Hirchaud Daniel Baron Caroline Benech Jeanne Guihot Morgane Placet Olivier Mignen Claude Férec Rémi Houlgatte Gaëlle Friocourt |
| author_facet | Marie-Lise Quillé Solenne Carat Sylvia Quéméner-Redon Edouard Hirchaud Daniel Baron Caroline Benech Jeanne Guihot Morgane Placet Olivier Mignen Claude Férec Rémi Houlgatte Gaëlle Friocourt |
| author_sort | Marie-Lise Quillé |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T14:25:02Z |
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| id | doaj.art-6a2df5e0c1a84f3cad42a19d62594d09 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T14:25:02Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6a2df5e0c1a84f3cad42a19d62594d092022-12-22T01:02:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0169e2518110.1371/journal.pone.0025181High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies.Marie-Lise QuilléSolenne CaratSylvia Quéméner-RedonEdouard HirchaudDaniel BaronCaroline BenechJeanne GuihotMorgane PlacetOlivier MignenClaude FérecRémi HoulgatteGaëlle FriocourtGenetic 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.http://europepmc.org/articles/PMC3178625?pdf=render |
| spellingShingle | Marie-Lise Quillé Solenne Carat Sylvia Quéméner-Redon Edouard Hirchaud Daniel Baron Caroline Benech Jeanne Guihot Morgane Placet Olivier Mignen Claude Férec Rémi Houlgatte Gaëlle Friocourt High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. PLoS ONE |
| title | High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. |
| title_full | High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. |
| title_fullStr | High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. |
| title_full_unstemmed | High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. |
| title_short | High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. |
| title_sort | high throughput analysis of promoter occupancy reveals new targets for arx a gene mutated in mental retardation and interneuronopathies |
| url | http://europepmc.org/articles/PMC3178625?pdf=render |
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