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Auteur Valerie W. HU |
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Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism / Valerie W. HU in Autism Research, 2-2 (April 2009)
[article]
Titre : Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism Type de document : Texte imprimé et/ou numérique Auteurs : Valerie W. HU, Auteur ; Mara E. STEINBERG, Auteur ; Tewarit SARACHANA, Auteur ; Kyung Soon KIM, Auteur ; AnhThu NGUYEN, Auteur ; Shreya KULKARNI, Auteur ; Truong LUU, Auteur ; Yinglei LAI, Auteur ; Norman H. LEE, Auteur Année de publication : 2009 Article en page(s) : p.78-97 Langues : Anglais (eng) Mots-clés : autism-phenotypes gene-expression-profiling circadian-rhythm novel-genes Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males. En ligne : http://dx.doi.org/10.1002/aur.73 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=936
in Autism Research > 2-2 (April 2009) . - p.78-97[article] Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism [Texte imprimé et/ou numérique] / Valerie W. HU, Auteur ; Mara E. STEINBERG, Auteur ; Tewarit SARACHANA, Auteur ; Kyung Soon KIM, Auteur ; AnhThu NGUYEN, Auteur ; Shreya KULKARNI, Auteur ; Truong LUU, Auteur ; Yinglei LAI, Auteur ; Norman H. LEE, Auteur . - 2009 . - p.78-97.
Langues : Anglais (eng)
in Autism Research > 2-2 (April 2009) . - p.78-97
Mots-clés : autism-phenotypes gene-expression-profiling circadian-rhythm novel-genes Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males. En ligne : http://dx.doi.org/10.1002/aur.73 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=936 Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder / Tewarit SARACHANA in Molecular Autism, (May 2013)
[article]
Titre : Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Tewarit SARACHANA, Auteur ; Valerie W. HU, Auteur Année de publication : 2013 Article en page(s) : 19 p. Langues : Anglais (eng) Mots-clés : RORA Autism Nuclear hormone receptor Transcriptional targets Chromatin immunoprecipitation Promoter microarray Index. décimale : PER Périodiques Résumé : BACKGROUND:We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans.METHODS:Here we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression.RESULTS:The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as development of the cortex and cerebellum, cognition, memory, and spatial learning. Independent ChIP-quantitative PCR analyses confirm binding of RORA1 to promoter regions of selected ASD-associated genes, including A2BP1, CYP19A1, ITPR1, NLGN1, and NTRK2, whose expression levels (in addition to HSD17B10) are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD.CONCLUSIONS:Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these ASD-relevant genes as well as their associated pathways and functions which, in turn, may contribute to the underlying pathobiology of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-14 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202
in Molecular Autism > (May 2013) . - 19 p.[article] Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder [Texte imprimé et/ou numérique] / Tewarit SARACHANA, Auteur ; Valerie W. HU, Auteur . - 2013 . - 19 p.
Langues : Anglais (eng)
in Molecular Autism > (May 2013) . - 19 p.
Mots-clés : RORA Autism Nuclear hormone receptor Transcriptional targets Chromatin immunoprecipitation Promoter microarray Index. décimale : PER Périodiques Résumé : BACKGROUND:We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans.METHODS:Here we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression.RESULTS:The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as development of the cortex and cerebellum, cognition, memory, and spatial learning. Independent ChIP-quantitative PCR analyses confirm binding of RORA1 to promoter regions of selected ASD-associated genes, including A2BP1, CYP19A1, ITPR1, NLGN1, and NTRK2, whose expression levels (in addition to HSD17B10) are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD.CONCLUSIONS:Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these ASD-relevant genes as well as their associated pathways and functions which, in turn, may contribute to the underlying pathobiology of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-14 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism / Valerie W. HU in Molecular Autism, (May 2015)
[article]
Titre : Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism Type de document : Texte imprimé et/ou numérique Auteurs : Valerie W. HU, Auteur ; Tewarit SARACHANA, Auteur ; Rachel M. SHERRARD, Auteur ; Kristen M. KOCHER, Auteur Article en page(s) : p.1-19 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant impairment in reciprocal social interactions and communication coupled with stereotyped, repetitive behaviors and restricted interests. Although genomic and functional studies are beginning to reveal some of the genetic complexity and underlying pathobiology of ASD, the consistently reported male bias of ASD remains an enigma. We have recently proposed that retinoic acid-related orphan receptor alpha (RORA), which is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with ASD and oppositely regulated by male and female hormones, might contribute to the sex bias in autism by differentially regulating target genes, including CYP19A1 (aromatase), in a sex-dependent manner that can also lead to elevated testosterone levels, a proposed risk factor for autism. En ligne : http://dx.doi.org/10.1186/2040-2392-6-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277
in Molecular Autism > (May 2015) . - p.1-19[article] Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism [Texte imprimé et/ou numérique] / Valerie W. HU, Auteur ; Tewarit SARACHANA, Auteur ; Rachel M. SHERRARD, Auteur ; Kristen M. KOCHER, Auteur . - p.1-19.
Langues : Anglais (eng)
in Molecular Autism > (May 2015) . - p.1-19
Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant impairment in reciprocal social interactions and communication coupled with stereotyped, repetitive behaviors and restricted interests. Although genomic and functional studies are beginning to reveal some of the genetic complexity and underlying pathobiology of ASD, the consistently reported male bias of ASD remains an enigma. We have recently proposed that retinoic acid-related orphan receptor alpha (RORA), which is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with ASD and oppositely regulated by male and female hormones, might contribute to the sex bias in autism by differentially regulating target genes, including CYP19A1 (aromatase), in a sex-dependent manner that can also lead to elevated testosterone levels, a proposed risk factor for autism. En ligne : http://dx.doi.org/10.1186/2040-2392-6-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders / Valerie W. HU in Autism Research, 2-2 (April 2009)
[article]
Titre : Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Valerie W. HU, Auteur ; Mara E. STEINBERG, Auteur Année de publication : 2009 Article en page(s) : p.67-77 Langues : Anglais (eng) Mots-clés : ADI-R multivariate-cluster-analyses ASD-phenotypes Index. décimale : PER Périodiques Résumé : Heterogeneity in phenotypic presentation of Autism spectrum disorders has been cited as one explanation for the difficulty in pinpointing specific genes involved in autism. Recent studies have attempted to reduce the noise in genetic and other biological data by reducing the phenotypic heterogeneity of the sample population. The current study employs multiple clustering algorithms on 123 item scores from the Autism Diagnostic Interview - Revised (ADI-R) diagnostic instrument of nearly 2,000 autistic individuals to identify subgroups of autistic probands with clinically relevant behavioral phenotypes in order to isolate more homogeneous groups of subjects for gene expression analyses. Our combined cluster analyses suggest optimal division of the autistic probands into four phenotypic clusters based on similarity of symptom severity across the 123 selected item scores. One cluster is characterized by severe language deficits, while another exhibits milder symptoms across the domains. A third group possesses a higher frequency of savant skills while the fourth group exhibited intermediate severity across all domains. Grouping autistic individuals by multivariate cluster analysis of ADI-R scores reveals meaningful phenotypes of subgroups within the autistic spectrum, which we show, in a related (accompanying) study, to be associated with distinct gene expression profiles. En ligne : http://dx.doi.org/10.1002/aur.72 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=936
in Autism Research > 2-2 (April 2009) . - p.67-77[article] Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders [Texte imprimé et/ou numérique] / Valerie W. HU, Auteur ; Mara E. STEINBERG, Auteur . - 2009 . - p.67-77.
Langues : Anglais (eng)
in Autism Research > 2-2 (April 2009) . - p.67-77
Mots-clés : ADI-R multivariate-cluster-analyses ASD-phenotypes Index. décimale : PER Périodiques Résumé : Heterogeneity in phenotypic presentation of Autism spectrum disorders has been cited as one explanation for the difficulty in pinpointing specific genes involved in autism. Recent studies have attempted to reduce the noise in genetic and other biological data by reducing the phenotypic heterogeneity of the sample population. The current study employs multiple clustering algorithms on 123 item scores from the Autism Diagnostic Interview - Revised (ADI-R) diagnostic instrument of nearly 2,000 autistic individuals to identify subgroups of autistic probands with clinically relevant behavioral phenotypes in order to isolate more homogeneous groups of subjects for gene expression analyses. Our combined cluster analyses suggest optimal division of the autistic probands into four phenotypic clusters based on similarity of symptom severity across the 123 selected item scores. One cluster is characterized by severe language deficits, while another exhibits milder symptoms across the domains. A third group possesses a higher frequency of savant skills while the fourth group exhibited intermediate severity across all domains. Grouping autistic individuals by multivariate cluster analysis of ADI-R scores reveals meaningful phenotypes of subgroups within the autistic spectrum, which we show, in a related (accompanying) study, to be associated with distinct gene expression profiles. En ligne : http://dx.doi.org/10.1002/aur.72 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=936