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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.

SUBMITTER: Banine F

PROVIDER: S-EPMC3261072 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Banine Fatima F Matagne Valerie V Sherman Larry S LS Ojeda Sergio R SR

Journal of neuroscience research 20110310 6

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, understandin ...[more]

PMID: 21394759

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Project description:MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs) within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum), whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute towards characterizing the expression profiles of Mecp2/MeCP2 isoforms and thereby provide insights on the potential role of MeCP2 isoforms in the developing and adult brain.

Dataset Information

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

Publications

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

Similar Datasets

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