Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene.
Identifieur interne : 002001 ( Main/Exploration ); précédent : 002000; suivant : 002002Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene.
Auteurs : Tessa Mattiske ; Kristie Lee ; Jozef Gecz ; Gaelle Friocourt [France] ; Cheryl ShoubridgeSource :
- Human molecular genetics [ 1460-2083 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Biosynthèse des protéines (génétique), Déficience intellectuelle (anatomopathologie), Déficience intellectuelle (génétique), Facteurs de transcription (génétique), Histone deacetylases (génétique), Humains, Modèles animaux de maladie humaine, Mutation, Peptides (génétique), Phénotype, Prosencéphale (embryologie), Prosencéphale (métabolisme), Protéines à homéodomaine (génétique), Régulation de l'expression des gènes au cours du développement, Souris, Transcriptome (génétique), Transduction du signal, Télencéphale (embryologie), Télencéphale (métabolisme), Épilepsie (anatomopathologie), Épilepsie (génétique).
- MESH :
- anatomopathologie : Déficience intellectuelle, Épilepsie.
- embryologie : Prosencéphale, Télencéphale.
- génétique : Biosynthèse des protéines, Déficience intellectuelle, Facteurs de transcription, Histone deacetylases, Peptides, Protéines à homéodomaine, Transcriptome, Épilepsie.
- métabolisme : Prosencéphale, Télencéphale.
- Animaux, Humains, Modèles animaux de maladie humaine, Mutation, Phénotype, Régulation de l'expression des gènes au cours du développement, Souris, Transduction du signal.
English descriptors
- KwdEn :
- Animals, Disease Models, Animal, Epilepsy (genetics), Epilepsy (pathology), Gene Expression Regulation, Developmental, Histone Deacetylases (genetics), Homeodomain Proteins (genetics), Humans, Intellectual Disability (genetics), Intellectual Disability (pathology), Mice, Mutation, Peptides (genetics), Phenotype, Prosencephalon (embryology), Prosencephalon (metabolism), Protein Biosynthesis (genetics), Signal Transduction, Telencephalon (embryology), Telencephalon (metabolism), Transcription Factors (genetics), Transcriptome (genetics).
- MESH :
- chemical , genetics : Histone Deacetylases, Homeodomain Proteins, Peptides, Transcription Factors.
- embryology : Prosencephalon, Telencephalon.
- genetics : Epilepsy, Intellectual Disability, Protein Biosynthesis, Transcriptome.
- metabolism : Prosencephalon, Telencephalon.
- pathology : Epilepsy, Intellectual Disability.
- Animals, Disease Models, Animal, Gene Expression Regulation, Developmental, Humans, Mice, Mutation, Phenotype, Signal Transduction.
Abstract
The Aristaless-related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in embryonic development. Mutations in ARX give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. To capture the genetics and molecular disruptions that underpin the ARX-associated clinical phenotypes, we undertook a transcriptome wide RNASeq approach to analyse developing (12.5 dpc) telencephalon of mice modelling two recurrent polyalanine expansion mutations with different phenotypic severities in the ARX gene. Here we report 238 genes significantly deregulated (Log2FC > +/-1.1, P-value <0.05) when both mutations are compared to wild-type (WT) animals. When each mutation is considered separately, a greater number of genes were deregulated in the severe PA1 mice (825) than in the PA2 animals (78). Analysing genes deregulated in either or both mutant strains, we identified 12% as implicated in ID, epilepsy and autism (99/858), with ∼5% of them as putative or known direct targets of ARX transcriptional regulation. We propose a core pathway of transcription regulators, including Hdac4, involved in chromatin condensation and transcriptional repression, and one of its targets, the transcription factor Twist1, as potential drivers of the ID and infantile spasms in patients with ARX polyalanine expansion mutations. We predict that the subsequent disturbance to this pathway is a consequence of ARX protein reduction with a broader and more significant level of disruption in the PA1 in comparison to the PA2 mice. Identifying early triggers of ARX-associated phenotypes contributes to our understanding of particular clusters/pathways underpinning comorbid phenotypes that are shared by many neurodevelopmental disorders.
DOI: 10.1093/hmg/ddw360
PubMed: 27798109
Affiliations:
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Le document en format XML
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Gecz</name><affiliation><nlm:affiliation>Department of Paediatrics, Adelaide Medical School.</nlm:affiliation><wicri:noCountry code="subField">Adelaide Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Friocourt, Gaelle" sort="Friocourt, Gaelle" uniqKey="Friocourt G" first="Gaelle" last="Friocourt">Gaelle Friocourt</name><affiliation wicri:level="3"><nlm:affiliation>Inserm, UMR1078, Brest, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, UMR1078, Brest</wicri:regionArea><placeName><region type="region">Région Bretagne</region><region type="old region">Région Bretagne</region><settlement type="city">Brest</settlement></placeName></affiliation></author><author><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name><affiliation><nlm:affiliation>Department of Paediatrics, Adelaide Medical School.</nlm:affiliation><wicri:noCountry code="subField">Adelaide Medical School</wicri:noCountry></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Epilepsy (genetics)</term><term>Epilepsy (pathology)</term><term>Gene Expression Regulation, Developmental</term><term>Histone Deacetylases (genetics)</term><term>Homeodomain Proteins (genetics)</term><term>Humans</term><term>Intellectual Disability (genetics)</term><term>Intellectual Disability (pathology)</term><term>Mice</term><term>Mutation</term><term>Peptides (genetics)</term><term>Phenotype</term><term>Prosencephalon (embryology)</term><term>Prosencephalon (metabolism)</term><term>Protein Biosynthesis (genetics)</term><term>Signal Transduction</term><term>Telencephalon (embryology)</term><term>Telencephalon (metabolism)</term><term>Transcription Factors (genetics)</term><term>Transcriptome (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Biosynthèse des protéines (génétique)</term><term>Déficience intellectuelle (anatomopathologie)</term><term>Déficience intellectuelle (génétique)</term><term>Facteurs de transcription (génétique)</term><term>Histone deacetylases (génétique)</term><term>Humains</term><term>Modèles animaux de maladie humaine</term><term>Mutation</term><term>Peptides (génétique)</term><term>Phénotype</term><term>Prosencéphale (embryologie)</term><term>Prosencéphale (métabolisme)</term><term>Protéines à homéodomaine (génétique)</term><term>Régulation de l'expression des gènes au cours du développement</term><term>Souris</term><term>Transcriptome (génétique)</term><term>Transduction du signal</term><term>Télencéphale (embryologie)</term><term>Télencéphale (métabolisme)</term><term>Épilepsie (anatomopathologie)</term><term>Épilepsie (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Histone Deacetylases</term><term>Homeodomain Proteins</term><term>Peptides</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Déficience intellectuelle</term><term>Épilepsie</term></keywords><keywords scheme="MESH" qualifier="embryologie" xml:lang="fr"><term>Prosencéphale</term><term>Télencéphale</term></keywords><keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Prosencephalon</term><term>Telencephalon</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Epilepsy</term><term>Intellectual Disability</term><term>Protein Biosynthesis</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Biosynthèse des protéines</term><term>Déficience intellectuelle</term><term>Facteurs de transcription</term><term>Histone deacetylases</term><term>Peptides</term><term>Protéines à homéodomaine</term><term>Transcriptome</term><term>Épilepsie</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Prosencephalon</term><term>Telencephalon</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Prosencéphale</term><term>Télencéphale</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Epilepsy</term><term>Intellectual Disability</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Gene Expression Regulation, Developmental</term><term>Humans</term><term>Mice</term><term>Mutation</term><term>Phenotype</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Modèles animaux de maladie humaine</term><term>Mutation</term><term>Phénotype</term><term>Régulation de l'expression des gènes au cours du développement</term><term>Souris</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Aristaless-related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in embryonic development. Mutations in ARX give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. To capture the genetics and molecular disruptions that underpin the ARX-associated clinical phenotypes, we undertook a transcriptome wide RNASeq approach to analyse developing (12.5 dpc) telencephalon of mice modelling two recurrent polyalanine expansion mutations with different phenotypic severities in the ARX gene. Here we report 238 genes significantly deregulated (Log2FC > +/-1.1, P-value <0.05) when both mutations are compared to wild-type (WT) animals. When each mutation is considered separately, a greater number of genes were deregulated in the severe PA1 mice (825) than in the PA2 animals (78). Analysing genes deregulated in either or both mutant strains, we identified 12% as implicated in ID, epilepsy and autism (99/858), with ∼5% of them as putative or known direct targets of ARX transcriptional regulation. We propose a core pathway of transcription regulators, including Hdac4, involved in chromatin condensation and transcriptional repression, and one of its targets, the transcription factor Twist1, as potential drivers of the ID and infantile spasms in patients with ARX polyalanine expansion mutations. We predict that the subsequent disturbance to this pathway is a consequence of ARX protein reduction with a broader and more significant level of disruption in the PA1 in comparison to the PA2 mice. Identifying early triggers of ARX-associated phenotypes contributes to our understanding of particular clusters/pathways underpinning comorbid phenotypes that are shared by many neurodevelopmental disorders.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Région Bretagne</li></region><settlement><li>Brest</li></settlement></list><tree><noCountry><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><name sortKey="Lee, Kristie" sort="Lee, Kristie" uniqKey="Lee K" first="Kristie" last="Lee">Kristie Lee</name><name sortKey="Mattiske, Tessa" sort="Mattiske, Tessa" uniqKey="Mattiske T" first="Tessa" last="Mattiske">Tessa Mattiske</name><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name></noCountry><country name="France"><region name="Région Bretagne"><name sortKey="Friocourt, Gaelle" sort="Friocourt, Gaelle" uniqKey="Friocourt G" first="Gaelle" last="Friocourt">Gaelle Friocourt</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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