Dépouillements

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism / Tewarit SARACHANA in Molecular Autism, (October 2013)  

Public ISBD [article]  inMolecular Autism > (October 2013) Titre : Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism Type de document : Texte imprimé et/ou numérique Auteurs : Tewarit SARACHANA, Auteur ; Valerie HU, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Our independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate RORA in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of RORA may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate RORA are still unknown. Here we use functional knockdown of hormone receptors and coregulators with small interfering RNA (siRNA) to investigate their involvement in sex hormone regulation of RORA in human neuronal cells. Luciferase assays using a vector containing various RORA promoter constructs were first performed to identify the promoter regions required for inverse regulation of RORA by male and female hormones. Sequential chromatin immunoprecipitation methods followed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses of RORA expression in hormone-treated SH-SY5Y cells were then utilized to identify coregulators that associate with hormone receptors on the RORA promoter. siRNA-mediated knockdown of interacting coregulators was performed followed by qRT-PCR analyses to confirm the functional requirement of each coregulator in hormone-regulated RORA expression. Our studies demonstrate the direct involvement of androgen receptor (AR) and estrogen receptor (ER) in the regulation of RORA by male and female hormones, respectively, and that the promoter region between 10055 bp and 2344 bp from the transcription start site of RORA is required for the inverse hormonal regulation. We further show that AR interacts with SUMO1, a reported suppressor of AR transcriptional activity, whereas ERalpha interacts with the coactivator NCOA5 on the RORA promoter. siRNA-mediated knockdown of SUMO1 and NCOA5 attenuate the sex hormone effects on RORA expression. AR and SUMO1 are involved in the suppression RORA expression by androgen, while ERalpha and NCOA5 collaborate in the up-regulation of RORA by estrogen. While this study offers a better understanding of molecular mechanisms involved in sex hormone regulation of RORA, it also reveals another layer of complexity with regard to gene regulation in ASD. Inasmuch as coregulators are capable of interacting with a multitude of transcription factors, aberrant expression of coregulator proteins, as we have seen previously in lymphoblasts from individuals with ASD, may contribute to the polygenic nature of gene dysregulation in ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-39 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism [Texte imprimé et/ou numérique] / Tewarit SARACHANA, Auteur ; Valerie HU, Auteur. Langues : Anglais (eng) in Molecular Autism > (October 2013) Index. décimale : PER Périodiques Résumé : Our independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate RORA in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of RORA may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate RORA are still unknown. Here we use functional knockdown of hormone receptors and coregulators with small interfering RNA (siRNA) to investigate their involvement in sex hormone regulation of RORA in human neuronal cells. Luciferase assays using a vector containing various RORA promoter constructs were first performed to identify the promoter regions required for inverse regulation of RORA by male and female hormones. Sequential chromatin immunoprecipitation methods followed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses of RORA expression in hormone-treated SH-SY5Y cells were then utilized to identify coregulators that associate with hormone receptors on the RORA promoter. siRNA-mediated knockdown of interacting coregulators was performed followed by qRT-PCR analyses to confirm the functional requirement of each coregulator in hormone-regulated RORA expression. Our studies demonstrate the direct involvement of androgen receptor (AR) and estrogen receptor (ER) in the regulation of RORA by male and female hormones, respectively, and that the promoter region between 10055 bp and 2344 bp from the transcription start site of RORA is required for the inverse hormonal regulation. We further show that AR interacts with SUMO1, a reported suppressor of AR transcriptional activity, whereas ERalpha interacts with the coactivator NCOA5 on the RORA promoter. siRNA-mediated knockdown of SUMO1 and NCOA5 attenuate the sex hormone effects on RORA expression. AR and SUMO1 are involved in the suppression RORA expression by androgen, while ERalpha and NCOA5 collaborate in the up-regulation of RORA by estrogen. While this study offers a better understanding of molecular mechanisms involved in sex hormone regulation of RORA, it also reveals another layer of complexity with regard to gene regulation in ASD. Inasmuch as coregulators are capable of interacting with a multitude of transcription factors, aberrant expression of coregulator proteins, as we have seen previously in lymphoblasts from individuals with ASD, may contribute to the polygenic nature of gene dysregulation in ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-39 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Atypical brain lateralisation in the auditory cortex and language performance in 3- to 7-year-old children with high-functioning autism spectrum disorder: a child-customised magnetoencephalography (MEG) study / Yuko YOSHIMURA in Molecular Autism, (October 2013)  

Public ISBD [article]  inMolecular Autism > (October 2013) Titre : Atypical brain lateralisation in the auditory cortex and language performance in 3- to 7-year-old children with high-functioning autism spectrum disorder: a child-customised magnetoencephalography (MEG) study Type de document : Texte imprimé et/ou numérique Auteurs : Yuko YOSHIMURA, Auteur ; Mitsuru KIKUCHI, Auteur ; Kiyomi SHITAMICHI, Auteur ; Sanae UENO, Auteur ; Toshio MUNESUE, Auteur ; Yasuki ONO, Auteur ; Tsunehisa TSUBOKAWA, Auteur ; Yasuhiro HARUTA, Auteur ; Manabu OI, Auteur ; Yo NIIDA, Auteur ; Gerard REMIJN, Auteur ; Tsutomu TAKAHASHI, Auteur ; Michio SUZUKI, Auteur ; Haruhiro HIGASHIDA, Auteur ; Yoshio MINABE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Magnetoencephalography (MEG) is used to measure the auditory evoked magnetic field (AEF), which reflects language-related performance. In young children, however, the simultaneous quantification of the bilateral auditory-evoked response during binaural hearing is difficult using conventional adult-sized MEG systems. Recently, a child-customised MEG device has facilitated the acquisition of bi-hemispheric recordings, even in young children. Using the child-customised MEG device, we previously reported that language-related performance was reflected in the strength of the early component (P50m) of the auditory evoked magnetic field (AEF) in typically developing (TD) young children (2 to 5 years old) [Eur J Neurosci 2012, 35:644-650]. The aim of this study was to investigate how this neurophysiological index in each hemisphere is correlated with language performance in autism spectrum disorder (ASD) and TD children. We used magnetoencephalography (MEG) to measure the auditory evoked magnetic field (AEF), which reflects language-related performance. We investigated the P50m that is evoked by voice stimuli (/ne/) bilaterally in 33 young children (3 to 7 years old) with ASD and in 30 young children who were typically developing (TD). The children were matched according to their age (in months) and gender. Most of the children with ASD were high-functioning subjects. The results showed that the children with ASD exhibited significantly less leftward lateralisation in their P50m intensity compared with the TD children. Furthermore, the results of a multiple regression analysis indicated that a shorter P50m latency in both hemispheres was specifically correlated with higher language-related performance in the TD children, whereas this latency was not correlated with non-verbal cognitive performance or chronological age. The children with ASD did not show any correlation between P50m latency and language-related performance; instead, increasing chronological age was a significant predictor of shorter P50m latency in the right hemisphere. Using a child-customised MEG device, we studied the P50m component that was evoked through binaural human voice stimuli in young ASD and TD children to examine differences in auditory cortex function that are associated with language development. Our results suggest that there is atypical brain function in the auditory cortex in young children with ASD, regardless of language development. En ligne : http://dx.doi.org/10.1186/2040-2392-4-38 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Atypical brain lateralisation in the auditory cortex and language performance in 3- to 7-year-old children with high-functioning autism spectrum disorder: a child-customised magnetoencephalography (MEG) study [Texte imprimé et/ou numérique] / Yuko YOSHIMURA, Auteur ; Mitsuru KIKUCHI, Auteur ; Kiyomi SHITAMICHI, Auteur ; Sanae UENO, Auteur ; Toshio MUNESUE, Auteur ; Yasuki ONO, Auteur ; Tsunehisa TSUBOKAWA, Auteur ; Yasuhiro HARUTA, Auteur ; Manabu OI, Auteur ; Yo NIIDA, Auteur ; Gerard REMIJN, Auteur ; Tsutomu TAKAHASHI, Auteur ; Michio SUZUKI, Auteur ; Haruhiro HIGASHIDA, Auteur ; Yoshio MINABE, Auteur. Langues : Anglais (eng) in Molecular Autism > (October 2013) Index. décimale : PER Périodiques Résumé : Magnetoencephalography (MEG) is used to measure the auditory evoked magnetic field (AEF), which reflects language-related performance. In young children, however, the simultaneous quantification of the bilateral auditory-evoked response during binaural hearing is difficult using conventional adult-sized MEG systems. Recently, a child-customised MEG device has facilitated the acquisition of bi-hemispheric recordings, even in young children. Using the child-customised MEG device, we previously reported that language-related performance was reflected in the strength of the early component (P50m) of the auditory evoked magnetic field (AEF) in typically developing (TD) young children (2 to 5 years old) [Eur J Neurosci 2012, 35:644-650]. The aim of this study was to investigate how this neurophysiological index in each hemisphere is correlated with language performance in autism spectrum disorder (ASD) and TD children. We used magnetoencephalography (MEG) to measure the auditory evoked magnetic field (AEF), which reflects language-related performance. We investigated the P50m that is evoked by voice stimuli (/ne/) bilaterally in 33 young children (3 to 7 years old) with ASD and in 30 young children who were typically developing (TD). The children were matched according to their age (in months) and gender. Most of the children with ASD were high-functioning subjects. The results showed that the children with ASD exhibited significantly less leftward lateralisation in their P50m intensity compared with the TD children. Furthermore, the results of a multiple regression analysis indicated that a shorter P50m latency in both hemispheres was specifically correlated with higher language-related performance in the TD children, whereas this latency was not correlated with non-verbal cognitive performance or chronological age. The children with ASD did not show any correlation between P50m latency and language-related performance; instead, increasing chronological age was a significant predictor of shorter P50m latency in the right hemisphere. Using a child-customised MEG device, we studied the P50m component that was evoked through binaural human voice stimuli in young ASD and TD children to examine differences in auditory cortex function that are associated with language development. Our results suggest that there is atypical brain function in the auditory cortex in young children with ASD, regardless of language development. En ligne : http://dx.doi.org/10.1186/2040-2392-4-38 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders / Roselyn ROSE'MEYER in Molecular Autism, (October 2013)  

Public ISBD [article]  inMolecular Autism > (October 2013) Titre : A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Roselyn ROSE'MEYER, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The diagnosis of autism spectrum disorder (ASD) during early childhood has a profound effect not only on young children but on their families. Aside from the physical and behavioural issues that need to be dealt with, there are significant emotional and financial costs associated with living with someone diagnosed with ASD. Understanding how autism occurs will assist in preparing families to deal with ASD, if not preventing or lessening its occurrence.Serotonin plays a vital role in the development of the brain during the prenatal and postnatal periods, yet very little is known about the serotonergic systems that affect children with ASD. This review seeks to provide an understanding of the biochemistry and physiological actions of serotonin and its termination of action through the serotonin reuptake transporter (SERT). Epidemiological studies investigating prenatal conditions that can increase the risk of ASD describe a number of factors which elevate plasma cortisol levels causing such symptoms during pregnancy such as hypertension, gestational diabetes and depression. Because cortisol plays an important role in driving dysregulation of serotonergic signalling through elevating SERT production in the developing brain, it is also necessary to investigate the physiological functions of cortisol, its action during gestation and metabolic syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-37 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders [Texte imprimé et/ou numérique] / Roselyn ROSE'MEYER, Auteur. Langues : Anglais (eng) in Molecular Autism > (October 2013) Index. décimale : PER Périodiques Résumé : The diagnosis of autism spectrum disorder (ASD) during early childhood has a profound effect not only on young children but on their families. Aside from the physical and behavioural issues that need to be dealt with, there are significant emotional and financial costs associated with living with someone diagnosed with ASD. Understanding how autism occurs will assist in preparing families to deal with ASD, if not preventing or lessening its occurrence.Serotonin plays a vital role in the development of the brain during the prenatal and postnatal periods, yet very little is known about the serotonergic systems that affect children with ASD. This review seeks to provide an understanding of the biochemistry and physiological actions of serotonin and its termination of action through the serotonin reuptake transporter (SERT). Epidemiological studies investigating prenatal conditions that can increase the risk of ASD describe a number of factors which elevate plasma cortisol levels causing such symptoms during pregnancy such as hypertension, gestational diabetes and depression. Because cortisol plays an important role in driving dysregulation of serotonergic signalling through elevating SERT production in the developing brain, it is also necessary to investigate the physiological functions of cortisol, its action during gestation and metabolic syndromes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-37 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs) / Brett ABRAHAMS in Molecular Autism, (October 2013)  

Public ISBD [article]  inMolecular Autism > (October 2013) Titre : SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs) Type de document : Texte imprimé et/ou numérique Auteurs : Brett ABRAHAMS, Auteur ; Dan ARKING, Auteur ; Daniel B. CAMPBELL, Auteur ; Heather MEFFORD, Auteur ; Eric MORROW, Auteur ; Lauren WEISS, Auteur ; Idan MENASHE, Auteur ; Tim WADKINS, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Alan PACKER, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-36 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs) [Texte imprimé et/ou numérique] / Brett ABRAHAMS, Auteur ; Dan ARKING, Auteur ; Daniel B. CAMPBELL, Auteur ; Heather MEFFORD, Auteur ; Eric MORROW, Auteur ; Lauren WEISS, Auteur ; Idan MENASHE, Auteur ; Tim WADKINS, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Alan PACKER, Auteur. Langues : Anglais (eng) in Molecular Autism > (October 2013) Index. décimale : PER Périodiques Résumé : New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-36 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice / Travis KERR in Molecular Autism, (October 2013)  

Public ISBD [article]  inMolecular Autism > (October 2013) Titre : Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice Type de document : Texte imprimé et/ou numérique Auteurs : Travis KERR, Auteur ; Christopher MULLER, Auteur ; Mahfuzur MIAH, Auteur ; Christopher JETTER, Auteur ; Rita PFEIFFER, Auteur ; Charisma SHAH, Auteur ; Nicole BAGANZ, Auteur ; George M. ANDERSON, Auteur ; Jacqueline N. CRAWLEY, Auteur ; James SUTCLIFFE, Auteur ; Randy BLAKELY, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans. En ligne : http://dx.doi.org/10.1186/2040-2392-4-35 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice [Texte imprimé et/ou numérique] / Travis KERR, Auteur ; Christopher MULLER, Auteur ; Mahfuzur MIAH, Auteur ; Christopher JETTER, Auteur ; Rita PFEIFFER, Auteur ; Charisma SHAH, Auteur ; Nicole BAGANZ, Auteur ; George M. ANDERSON, Auteur ; Jacqueline N. CRAWLEY, Auteur ; James SUTCLIFFE, Auteur ; Randy BLAKELY, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur. Langues : Anglais (eng) in Molecular Autism > (October 2013) Index. décimale : PER Périodiques Résumé : Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans. En ligne : http://dx.doi.org/10.1186/2040-2392-4-35 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227