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

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