Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms

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    Abstract

    Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones.

    Original languageEnglish (US)
    Pages (from-to)840-851
    Number of pages12
    JournalJournal of Neuroscience Research
    Volume89
    Issue number6
    DOIs
    StatePublished - Jun 2011

    Fingerprint

    Methyl-CpG-Binding Protein 2
    Frontal Lobe
    Epigenomics
    Cerebellum
    Histones
    Brain
    Genes
    DNA Methylation
    Messenger RNA
    Lysine
    Histone Code
    Rett Syndrome
    Genetic Promoter Regions
    Protein Binding
    Protein Kinases
    Membrane Proteins
    Mutation

    Keywords

    • DNA methylation
    • Histone acetylation
    • Phospholemman
    • Rett syndrome

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience

    Cite this

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    title = "Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms",
    abstract = "Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones.",
    keywords = "DNA methylation, Histone acetylation, Phospholemman, Rett syndrome",
    author = "Fatima Banine and Valerie Matagne and Sherman, {Lawrence (Larry)} and Sergio Ojeda",
    year = "2011",
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    doi = "10.1002/jnr.22608",
    language = "English (US)",
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    TY - JOUR

    T1 - Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms

    AU - Banine, Fatima

    AU - Matagne, Valerie

    AU - Sherman, Lawrence (Larry)

    AU - Ojeda, Sergio

    PY - 2011/6

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    N2 - Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones.

    AB - Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones.

    KW - DNA methylation

    KW - Histone acetylation

    KW - Phospholemman

    KW - Rett syndrome

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