Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism / Amber HOGART

Public ISBD contenu dans The Neurochemical Basis of Autism / Gene J. BLATT Titre : Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism Type de document : Texte imprimé et/ou numérique Auteurs : Amber HOGART, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2010 Importance : p.113-127 Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=109 contenu dans The Neurochemical Basis of Autism / Gene J. BLATT Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism [Texte imprimé et/ou numérique] / Amber HOGART, Auteur ; Janine M. LASALLE, Auteur . - 2010 . - p.113-127. Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=109

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Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples / Haley SCOLES in Molecular Autism, (December 2011)  

Public ISBD [article]  inMolecular Autism > (December 2011) . - 41 p. Titre : Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples Type de document : Texte imprimé et/ou numérique Auteurs : Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence REITER, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2011 Article en page(s) : 41 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 [article] Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples [Texte imprimé et/ou numérique] / Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence REITER, Auteur ; Janine M. LASALLE, Auteur . - 2011 . - 41 p. Langues : Anglais (eng) in Molecular Autism > (December 2011) . - 41 p. Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149

MeCP2 and Autism Spectrum Disorders / Sarrita ADAMS

Public ISBD in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Titre : MeCP2 and Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Sarrita ADAMS, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2013 Importance : p.421-436 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are characterized by complex genetic etiologies. Within ASD are a number of syndromic disorders with known genetic bases and autistic features. Rett syndrome (RTT) is an X-linked dominant ASD caused by mutations in the DNA methyl-binding protein MeCP2. A variety of mouse models of MeCP2 deficiency and over-expression have been generated and revealed the role of MeCP2 at the center of a number of other ASD-relevant pathways controlling synapse number and strength. In this chapter, we review the evidence for overlap in MeCP2 function with other ASD implicated genes, including FMR1, MEF2C, FOXG1, CNTNAP2, SHANK3, TSC2, UBE3A, and SYN1. In addition, we discuss what mouse models with these genetic deficiencies have revealed about the specific deficits of synaptic function in ASD and the normal orchestration of synaptic plasticity in the early postnatal brain. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM MeCP2 and Autism Spectrum Disorders [Texte imprimé et/ou numérique] / Sarrita ADAMS, Auteur ; Janine M. LASALLE, Auteur . - 2013 . - p.421-436. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are characterized by complex genetic etiologies. Within ASD are a number of syndromic disorders with known genetic bases and autistic features. Rett syndrome (RTT) is an X-linked dominant ASD caused by mutations in the DNA methyl-binding protein MeCP2. A variety of mouse models of MeCP2 deficiency and over-expression have been generated and revealed the role of MeCP2 at the center of a number of other ASD-relevant pathways controlling synapse number and strength. In this chapter, we review the evidence for overlap in MeCP2 function with other ASD implicated genes, including FMR1, MEF2C, FOXG1, CNTNAP2, SHANK3, TSC2, UBE3A, and SYN1. In addition, we discuss what mouse models with these genetic deficiencies have revealed about the specific deficits of synaptic function in ASD and the normal orchestration of synaptic plasticity in the early postnatal brain. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

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MeCP2 modulates gene expression pathways in astrocytes / Dag H. YASUI in Molecular Autism, (January 2013)  

Public ISBD [article]  inMolecular Autism > (January 2013) . - 11 p. Titre : MeCP2 modulates gene expression pathways in astrocytes Type de document : Texte imprimé et/ou numérique Auteurs : Dag H. YASUI, Auteur ; Huichun XU, Auteur ; Keith DUNAWAY, Auteur ; Janine M. LASALLE, Auteur ; Lee-Way JIN, Auteur ; Izumi MAEZAWA, Auteur Année de publication : 2013 Article en page(s) : 11 p. Mots-clés : MeCP2  Epigenetics  Astrocytes  Rett syndrome  ChIP-seq  Transcription Factors/chemistry/genetics Index. décimale : PER Périodiques Résumé : BACKGROUND:Mutations in MECP2 encoding methyl-CpG-binding protein 2 (MeCP2) cause the X-linked neurodevelopmental disorder Rett syndrome. Rett syndrome patients exhibit neurological symptoms that include irregular breathing, impaired mobility, stereotypic hand movements, and loss of speech. MeCP2 protein epigenetically modulates gene expression through genome-wide binding to methylated CpG dinucleotides. While neurons have the highest level of MeCP2 expression, astrocytes and other cell types also express detectable levels of MeCP2. Recent studies suggest that astrocytes likely control the progression of Rett syndrome. Thus, the object of these studies was to identify gene targets that are affected by loss of MeCP2 binding in astrocytes.METHODS:To identify gene targets of MeCP2 in astrocytes, combined approaches of expression microarray and chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) were compared between wild-type and MeCP2-deficient astrocytes. MeCP2 gene targets were compared with genes in the top 10% of MeCP2 binding levels in gene windows either within 2 kb upstream of the transcription start site, or the 'gene body' that extended from transcription start to end site, or 2 kb downstream of the transcription end site.RESULTS:A total of 118 gene transcripts surpassed the highly significant threshold (P 0.005, fold change 1.2) in expression microarray analysis from triplicate cultures. The top 10% of genes with the highest levels of MeCP2 binding were identified in two independent ChIP-seq experiments. Together this integrated, genome-wide screen for MeCP2 target genes provided an overlapping list of 19 high-confidence MeCP2-responsive gene transcripts in astrocytes. Validation of candidate target gene transcripts by RT-PCR revealed that expression of Apoc2, Cdon, Csrp and Nrep were consistently responsive to MeCP2 deficiency in astrocytes.CONCLUSIONS:The first MeCP2 ChIP-seq and gene expression microarray analysis in astrocytes reveals a set of potential MeCP2 target genes that may contribute to normal astrocyte signaling, cell division and neuronal support functions, the loss of which may contribute to the Rett syndrome phenotype. En ligne : http://dx.doi.org/10.1186/2040-2392-4-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] MeCP2 modulates gene expression pathways in astrocytes [Texte imprimé et/ou numérique] / Dag H. YASUI, Auteur ; Huichun XU, Auteur ; Keith DUNAWAY, Auteur ; Janine M. LASALLE, Auteur ; Lee-Way JIN, Auteur ; Izumi MAEZAWA, Auteur . - 2013 . - 11 p. in Molecular Autism > (January 2013) . - 11 p. Mots-clés : MeCP2  Epigenetics  Astrocytes  Rett syndrome  ChIP-seq  Transcription Factors/chemistry/genetics Index. décimale : PER Périodiques Résumé : BACKGROUND:Mutations in MECP2 encoding methyl-CpG-binding protein 2 (MeCP2) cause the X-linked neurodevelopmental disorder Rett syndrome. Rett syndrome patients exhibit neurological symptoms that include irregular breathing, impaired mobility, stereotypic hand movements, and loss of speech. MeCP2 protein epigenetically modulates gene expression through genome-wide binding to methylated CpG dinucleotides. While neurons have the highest level of MeCP2 expression, astrocytes and other cell types also express detectable levels of MeCP2. Recent studies suggest that astrocytes likely control the progression of Rett syndrome. Thus, the object of these studies was to identify gene targets that are affected by loss of MeCP2 binding in astrocytes.METHODS:To identify gene targets of MeCP2 in astrocytes, combined approaches of expression microarray and chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) were compared between wild-type and MeCP2-deficient astrocytes. MeCP2 gene targets were compared with genes in the top 10% of MeCP2 binding levels in gene windows either within 2 kb upstream of the transcription start site, or the 'gene body' that extended from transcription start to end site, or 2 kb downstream of the transcription end site.RESULTS:A total of 118 gene transcripts surpassed the highly significant threshold (P 0.005, fold change 1.2) in expression microarray analysis from triplicate cultures. The top 10% of genes with the highest levels of MeCP2 binding were identified in two independent ChIP-seq experiments. Together this integrated, genome-wide screen for MeCP2 target genes provided an overlapping list of 19 high-confidence MeCP2-responsive gene transcripts in astrocytes. Validation of candidate target gene transcripts by RT-PCR revealed that expression of Apoc2, Cdon, Csrp and Nrep were consistently responsive to MeCP2 deficiency in astrocytes.CONCLUSIONS:The first MeCP2 ChIP-seq and gene expression microarray analysis in astrocytes reveals a set of potential MeCP2 target genes that may contribute to normal astrocyte signaling, cell division and neuronal support functions, the loss of which may contribute to the Rett syndrome phenotype. En ligne : http://dx.doi.org/10.1186/2040-2392-4-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

MECP2 promoter methylation and X chromosome inactivation in autism / Raman P. NAGARAJAN in Autism Research, 1-3 (June 2008)  

Public ISBD [article]  inAutism Research > 1-3 (June 2008) . - p.169-178 Titre : MECP2 promoter methylation and X chromosome inactivation in autism Type de document : Texte imprimé et/ou numérique Auteurs : Raman P. NAGARAJAN, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Wendy P. ROBINSON, Auteur ; Ruby JIANG, Auteur ; Susan E. SWANBERG, Auteur ; Dag H. YASUI, Auteur ; Michelle MARTIN, Auteur ; Katherine A. PATZEL, Auteur ; Janine M. LASALLE, Auteur ; Judy VAN DE WATER, Auteur ; Isaac N. PESSAH, Auteur ; David J. HANSEN, Auteur Année de publication : 2008 Article en page(s) : p.169-178 Langues : Anglais (eng) Mots-clés : epigenetics X-chromosome-inactivation MECP2 postmortem-brain Index. décimale : PER Périodiques Résumé : Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were performed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCCTC-binding factor (CTCF) is bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes. En ligne : http://dx.doi.org/10.1002/aur.24 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=931 [article] MECP2 promoter methylation and X chromosome inactivation in autism [Texte imprimé et/ou numérique] / Raman P. NAGARAJAN, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Wendy P. ROBINSON, Auteur ; Ruby JIANG, Auteur ; Susan E. SWANBERG, Auteur ; Dag H. YASUI, Auteur ; Michelle MARTIN, Auteur ; Katherine A. PATZEL, Auteur ; Janine M. LASALLE, Auteur ; Judy VAN DE WATER, Auteur ; Isaac N. PESSAH, Auteur ; David J. HANSEN, Auteur . - 2008 . - p.169-178. Langues : Anglais (eng) in Autism Research > 1-3 (June 2008) . - p.169-178 Mots-clés : epigenetics X-chromosome-inactivation MECP2 postmortem-brain Index. décimale : PER Périodiques Résumé : Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were performed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCCTC-binding factor (CTCF) is bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes. En ligne : http://dx.doi.org/10.1002/aur.24 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=931

Rett syndrome : a Rosetta stone for understanding the molecular pathogenesis of autism / Janine M. LASALLE

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