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Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE123373 | GEO | 2019/11/26

REPOSITORIES: GEO

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Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (Bisulfite-Seq)

Project description:The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation at genes are established and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here we find that genes repressed by MeCP2 are found within regions of high non-CG methylation that are defined by domains of chromatin folding. Rather than working directly at transcriptional start sites to regulate these genes, MeCP2 represses enhancer elements that are enriched for methylated cytosines occurring in the CA or CG context. Enhancers repressed by MeCP2 are found within genes that are upregulated upon loss of the protein, providing a regulatory logic for how disruption of MeCP2 can lead to wide-spread changes in gene expression. Hence, we have found that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain.

2019-11-26 | GSE138613 | GEO

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (RNA-Seq)

2019-11-26 | GSE123372 | GEO

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (ChIP-Seq)

2019-11-26 | GSE123371 | GEO

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression

Project description:Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression

| PRJNA508525 | ENA

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (Bisulfite-Seq)

Project description:Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (Bisulfite-Seq)

| PRJNA576509 | ENA

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (ChIP-Seq)

Project description:Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (ChIP-Seq)

| PRJNA508527 | ENA

Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (RNA-Seq)

Project description:Chromosome topology shapes neuronal non-CG DNA methylation to influence MeCP2-mediated enhancer repression (RNA-Seq)

| PRJNA508528 | ENA

Neuronal non-CG methylation is an essential target for MeCP2 function.

Project description:DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype.

| S-EPMC7980222 | biostudies-literature

MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation.

Project description:The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain.

| S-EPMC6980697 | biostudies-literature

Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology.

Project description:The neurodevelopmental disorder Rett syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG-binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous, resulting from a lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease is unknown. We found that the loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brains. Using an in vitro co-culture system, we found that mutant astrocytes from a RTT mouse model, and their conditioned medium, failed to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that astrocytes in the RTT brain carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, probably as a result of aberrant secretion of soluble factor(s).

| S-EPMC3134296 | biostudies-literature

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