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Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons / E. M. A. LEWIS in Molecular Autism, 10 (2019)
[article]
Titre : Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur Article en page(s) : 51 p. Langues : Anglais (eng) Mots-clés : Cortical excitatory neurons Cortical inhibitory neurons Gene networks Multiplex autism Neurodevelopment Transcriptomics iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414
in Molecular Autism > 10 (2019) . - 51 p.[article] Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons [Texte imprimé et/ou numérique] / E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur . - 51 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 51 p.
Mots-clés : Cortical excitatory neurons Cortical inhibitory neurons Gene networks Multiplex autism Neurodevelopment Transcriptomics iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally / C. E. BARRETT in Molecular Autism, 8 (2017)
[article]
Titre : Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally Type de document : Texte imprimé et/ou numérique Auteurs : C. E. BARRETT, Auteur ; T. M. HENNESSEY, Auteur ; K. M. GORDON, Auteur ; S. J. RYAN, Auteur ; M. L. MCNAIR, Auteur ; K. J. RESSLER, Auteur ; D. G. RAINNIE, Auteur Article en page(s) : 42p. Langues : Anglais (eng) Mots-clés : Autism Basolateral amygdala Protein kinase A Proteomics RNA sequencing Social behavior Transcriptomics Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. METHODS: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. RESULTS: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. CONCLUSIONS: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. En ligne : http://dx.doi.org/10.1186/s13229-017-0160-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329
in Molecular Autism > 8 (2017) . - 42p.[article] Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally [Texte imprimé et/ou numérique] / C. E. BARRETT, Auteur ; T. M. HENNESSEY, Auteur ; K. M. GORDON, Auteur ; S. J. RYAN, Auteur ; M. L. MCNAIR, Auteur ; K. J. RESSLER, Auteur ; D. G. RAINNIE, Auteur . - 42p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 42p.
Mots-clés : Autism Basolateral amygdala Protein kinase A Proteomics RNA sequencing Social behavior Transcriptomics Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. METHODS: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. RESULTS: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. CONCLUSIONS: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. En ligne : http://dx.doi.org/10.1186/s13229-017-0160-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation / A. SAFFARI in Molecular Autism, 10 (2019)
[article]
Titre : RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation Type de document : Texte imprimé et/ou numérique Auteurs : A. SAFFARI, Auteur ; M. ARNO, Auteur ; E. NASSER, Auteur ; A. RONALD, Auteur ; C. C. Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; J. MILL, Auteur ; F. DUDBRIDGE, Auteur ; E. L. MEABURN, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder DNA methylation Discordance Epigenomics Gene expression Immune MZ twins RNA-seq Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414
in Molecular Autism > 10 (2019) . - 38 p.[article] RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation [Texte imprimé et/ou numérique] / A. SAFFARI, Auteur ; M. ARNO, Auteur ; E. NASSER, Auteur ; A. RONALD, Auteur ; C. C. Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; J. MILL, Auteur ; F. DUDBRIDGE, Auteur ; E. L. MEABURN, Auteur . - 38 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 38 p.
Mots-clés : Autism spectrum disorder DNA methylation Discordance Epigenomics Gene expression Immune MZ twins RNA-seq Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons / Catarina M. SEABRA in Molecular Autism, 11 (2020)
[article]
Titre : Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur Article en page(s) : 45 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 45 p.[article] Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons [Texte imprimé et/ou numérique] / Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur . - 45 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 45 p.
Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427