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A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood / C. E. MORDAUNT in Molecular Autism, 10 (2019)
[article]
Titre : A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood Type de document : Texte imprimé et/ou numérique Auteurs : C. E. MORDAUNT, Auteur ; B. Y. PARK, Auteur ; K. M. BAKULSKI, Auteur ; J. I. FEINBERG, Auteur ; Lisa A. CROEN, Auteur ; Christine LADD-ACOSTA, Auteur ; C. J. NEWSCHAFFER, Auteur ; Heather E. VOLK, Auteur ; S. OZONOFF, Auteur ; I. HERTZ-PICCIOTTO, Auteur ; J. M. LASALLE, Auteur ; Rebecca J. SCHMIDT, Auteur ; M. D. FALLIN, Auteur Article en page(s) : 36 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Chromatin Environment Gene expression Meta-analysis Microarray Neurodevelopment Perinatal Prospective study Umbilical cord blood Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children. Methods: Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis. Results: While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions. Limitations: ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder. Conclusions: This is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology. En ligne : http://dx.doi.org/10.1186/s13229-019-0287-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414
in Molecular Autism > 10 (2019) . - 36 p.[article] A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood [Texte imprimé et/ou numérique] / C. E. MORDAUNT, Auteur ; B. Y. PARK, Auteur ; K. M. BAKULSKI, Auteur ; J. I. FEINBERG, Auteur ; Lisa A. CROEN, Auteur ; Christine LADD-ACOSTA, Auteur ; C. J. NEWSCHAFFER, Auteur ; Heather E. VOLK, Auteur ; S. OZONOFF, Auteur ; I. HERTZ-PICCIOTTO, Auteur ; J. M. LASALLE, Auteur ; Rebecca J. SCHMIDT, Auteur ; M. D. FALLIN, Auteur . - 36 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 36 p.
Mots-clés : Autism spectrum disorder Chromatin Environment Gene expression Meta-analysis Microarray Neurodevelopment Perinatal Prospective study Umbilical cord blood Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children. Methods: Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis. Results: While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions. Limitations: ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder. Conclusions: This is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology. En ligne : http://dx.doi.org/10.1186/s13229-019-0287-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients / Yanyan QIAN in Journal of Autism and Developmental Disorders, 52-11 (November 2022)
[article]
Titre : Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients Type de document : Texte imprimé et/ou numérique Auteurs : Yanyan QIAN, Auteur ; Yuanfeng ZHOU, Auteur ; Bingbing WU, Auteur ; Huiyao CHEN, Auteur ; Suzhen XU, Auteur ; Yao WANG, Auteur ; Ping ZHANG, Auteur ; Gang LI, Auteur ; Qiong XU, Auteur ; Wenhao ZHOU, Auteur ; Xiu XU, Auteur ; Huijun WANG, Auteur Article en page(s) : p.5033-5041 Langues : Anglais (eng) Mots-clés : Abnormalities, Multiple Autism Spectrum Disorder Autistic Disorder/genetics China Chromatin DNA Helicases/genetics Face/abnormalities Hand Deformities, Congenital Humans Intellectual Disability/genetics Micrognathism Neck/abnormalities Nuclear Proteins/genetics Transcription Factors/genetics Autism spectrum disorder Coffin-Siris syndrome Neurodevelopmental-related disorders Phenotype Smarca4 Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing. En ligne : http://dx.doi.org/10.1007/s10803-021-05365-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489
in Journal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.5033-5041[article] Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients [Texte imprimé et/ou numérique] / Yanyan QIAN, Auteur ; Yuanfeng ZHOU, Auteur ; Bingbing WU, Auteur ; Huiyao CHEN, Auteur ; Suzhen XU, Auteur ; Yao WANG, Auteur ; Ping ZHANG, Auteur ; Gang LI, Auteur ; Qiong XU, Auteur ; Wenhao ZHOU, Auteur ; Xiu XU, Auteur ; Huijun WANG, Auteur . - p.5033-5041.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 52-11 (November 2022) . - p.5033-5041
Mots-clés : Abnormalities, Multiple Autism Spectrum Disorder Autistic Disorder/genetics China Chromatin DNA Helicases/genetics Face/abnormalities Hand Deformities, Congenital Humans Intellectual Disability/genetics Micrognathism Neck/abnormalities Nuclear Proteins/genetics Transcription Factors/genetics Autism spectrum disorder Coffin-Siris syndrome Neurodevelopmental-related disorders Phenotype Smarca4 Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing. En ligne : http://dx.doi.org/10.1007/s10803-021-05365-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=489 Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development / S. HURLEY in Molecular Autism, 12 (2021)
[article]
Titre : Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Type de document : Texte imprimé et/ou numérique Auteurs : S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 16 p.[article] Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development [Texte imprimé et/ou numérique] / S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur . - 16 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 16 p.
Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 Neurobehavioral Testing of Mouse Models of Rett Syndrome / Jean-Christophe ROUX
Titre : Neurobehavioral Testing of Mouse Models of Rett Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Jean-Christophe ROUX, Auteur ; Laurent VILLARD, Auteur Année de publication : 2015 Importance : p.399-430 Langues : Anglais (eng) Mots-clés : Rett syndrome Mecp2 Chromatin Methylation Brain Mouse model Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 Neurobehavioral Testing of Mouse Models of Rett Syndrome [Texte imprimé et/ou numérique] / Jean-Christophe ROUX, Auteur ; Laurent VILLARD, Auteur . - 2015 . - p.399-430.
Langues : Anglais (eng)
Mots-clés : Rett syndrome Mecp2 Chromatin Methylation Brain Mouse model Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 Exemplaires
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