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RNA sequencing of transformed lymphoblastoid cells from siblings discordant for autism spectrum disorders reveals transcriptomic and functional alterations: Evidence for sex-specific effects / Daniel S. TYLEE in Autism Research, 10-3 (March 2017)
[article]
Titre : RNA sequencing of transformed lymphoblastoid cells from siblings discordant for autism spectrum disorders reveals transcriptomic and functional alterations: Evidence for sex-specific effects Type de document : Texte imprimé et/ou numérique Auteurs : Daniel S. TYLEE, Auteur ; Alfred J. ESPINOZA, Auteur ; Jonathan L. HESS, Auteur ; Muhammad A. TAHIR, Auteur ; Sarah Y. MCCOY, Auteur ; Joshua K. RIM, Auteur ; Totadri DHIMAL, Auteur ; Ori S. COHEN, Auteur ; Stephen J. GLATT, Auteur Article en page(s) : p.439-455 Langues : Anglais (eng) Mots-clés : RNA sequencing transcriptome lymphoblastoid autism spectrum disorder sex-differences biomarker Index. décimale : PER Périodiques Résumé : Genome-wide expression studies of samples derived from individuals with autism spectrum disorder (ASD) and their unaffected siblings have been widely used to shed light on transcriptomic differences associated with this condition. Females have historically been under-represented in ASD genomic studies. Emerging evidence from studies of structural genetic variants and peripheral biomarkers suggest that sex-differences may exist in the biological correlates of ASD. Relatively few studies have explicitly examined whether sex-differences exist in the transcriptomic signature of ASD. The present study quantified genome-wide expression values by performing RNA sequencing on transformed lymphoblastoid cell lines and identified transcripts differentially expressed between same-sex, proximal-aged sibling pairs. We found that performing separate analyses for each sex improved our ability to detect ASD-related transcriptomic differences; we observed a larger number of dysregulated genes within our smaller set of female samples (n?=?12 sibling pairs), as compared with the set of male samples (n?=?24 sibling pairs), with small, but statistically significant overlap between the sexes. Permutation-based gene-set analyses and weighted gene co-expression network analyses also supported the idea that the transcriptomic signature of ASD may differ between males and females. We discuss our findings in the context of the relevant literature, underscoring the need for future ASD studies to explicitly account for differences between the sexes. En ligne : http://dx.doi.org/10.1002/aur.1679 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=304
in Autism Research > 10-3 (March 2017) . - p.439-455[article] RNA sequencing of transformed lymphoblastoid cells from siblings discordant for autism spectrum disorders reveals transcriptomic and functional alterations: Evidence for sex-specific effects [Texte imprimé et/ou numérique] / Daniel S. TYLEE, Auteur ; Alfred J. ESPINOZA, Auteur ; Jonathan L. HESS, Auteur ; Muhammad A. TAHIR, Auteur ; Sarah Y. MCCOY, Auteur ; Joshua K. RIM, Auteur ; Totadri DHIMAL, Auteur ; Ori S. COHEN, Auteur ; Stephen J. GLATT, Auteur . - p.439-455.
Langues : Anglais (eng)
in Autism Research > 10-3 (March 2017) . - p.439-455
Mots-clés : RNA sequencing transcriptome lymphoblastoid autism spectrum disorder sex-differences biomarker Index. décimale : PER Périodiques Résumé : Genome-wide expression studies of samples derived from individuals with autism spectrum disorder (ASD) and their unaffected siblings have been widely used to shed light on transcriptomic differences associated with this condition. Females have historically been under-represented in ASD genomic studies. Emerging evidence from studies of structural genetic variants and peripheral biomarkers suggest that sex-differences may exist in the biological correlates of ASD. Relatively few studies have explicitly examined whether sex-differences exist in the transcriptomic signature of ASD. The present study quantified genome-wide expression values by performing RNA sequencing on transformed lymphoblastoid cell lines and identified transcripts differentially expressed between same-sex, proximal-aged sibling pairs. We found that performing separate analyses for each sex improved our ability to detect ASD-related transcriptomic differences; we observed a larger number of dysregulated genes within our smaller set of female samples (n?=?12 sibling pairs), as compared with the set of male samples (n?=?24 sibling pairs), with small, but statistically significant overlap between the sexes. Permutation-based gene-set analyses and weighted gene co-expression network analyses also supported the idea that the transcriptomic signature of ASD may differ between males and females. We discuss our findings in the context of the relevant literature, underscoring the need for future ASD studies to explicitly account for differences between the sexes. En ligne : http://dx.doi.org/10.1002/aur.1679 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=304 CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes / C. FRICANO-KUGLER in Molecular Autism, 10 (2019)
[article]
Titre : CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : C. FRICANO-KUGLER, Auteur ; A. GORDON, Auteur ; G. SHIN, Auteur ; K. GAO, Auteur ; J. NGUYEN, Auteur ; J. BERG, Auteur ; M. STARKS, Auteur ; D. H. GESCHWIND, Auteur Article en page(s) : 25p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD) Cyfip1 Dup15q Fear conditioning Mouse behavior Neurodevelopmental disorders RNA sequencing Index. décimale : PER Périodiques Résumé : Background: CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods: We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results: Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion: Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. En ligne : http://dx.doi.org/10.1186/s13229-019-0278-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402
in Molecular Autism > 10 (2019) . - 25p.[article] CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes [Texte imprimé et/ou numérique] / C. FRICANO-KUGLER, Auteur ; A. GORDON, Auteur ; G. SHIN, Auteur ; K. GAO, Auteur ; J. NGUYEN, Auteur ; J. BERG, Auteur ; M. STARKS, Auteur ; D. H. GESCHWIND, Auteur . - 25p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 25p.
Mots-clés : Autism spectrum disorder (ASD) Cyfip1 Dup15q Fear conditioning Mouse behavior Neurodevelopmental disorders RNA sequencing Index. décimale : PER Périodiques Résumé : Background: CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods: We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results: Extensive behavioral testing in CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes, and myelination. We also identified GABA-A subunit composition changes in basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion: Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. En ligne : http://dx.doi.org/10.1186/s13229-019-0278-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 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 Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome / T. D. ROGERS in Molecular Autism, 8 (2017)
[article]
Titre : Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur Article en page(s) : 30p. Langues : Anglais (eng) Mots-clés : Amygdala Autism spectrum disorder Fragile X syndrome Prefrontal cortex RNA sequencing Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 30p.[article] Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome [Texte imprimé et/ou numérique] / T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur . - 30p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 30p.
Mots-clés : Amygdala Autism spectrum disorder Fragile X syndrome Prefrontal cortex RNA sequencing Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330