Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DNA methylation in the gene body influences MeCP2-mediated gene repression

ABSTRACT: Rett syndrome is a severe neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG-binding protein gene, MECP2. MeCP2 is a methyl-cytosine binding protein that is proposed to function as a transcriptional repressor. However, multiple gene expression studies comparing wild-type and MeCP2-deficient neurons have failed to identify gene expression changes consistent with loss of a classical transcriptional repressor. Recent work suggests that one function of MeCP2 in neurons is to temper the expression of the longest genes in the genome by binding to methylated CA dinucleotides (mCA) within transcribed regions of these genes. In the present study, we explore the mechanism of mCA and MeCP2 in fine-tuning the expression of long genes. We find that mCA is not only highly enriched within the body of genes normally repressed by MeCP2, but also enriched within extended megabase-scale regions surrounding MeCP2-repressed genes. While enrichment of mCA exists in a broad region around these genes, mCA within gene bodies appears to be the primary driver of gene repression by MeCP2. Disruption of methylation at CA sites within the brain results in depletion of MeCP2 across genes that normally contain a high density of gene-body mCA. We further find that the degree of gene repression by MeCP2 is proportional to the total number of methylated cytosine MeCP2 binding sites across the body of a gene. These findings suggest a model in which MeCP2 tunes gene expression in neurons by binding within the transcribed regions of genes to impede the elongation of RNA polymerase.

ORGANISM(S): Mus musculus

PROVIDER: GSE90704 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA355566

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Swapping the DNA binding domain of MeCP2 with that of MBD2 to abolish binding to non-CG methlyation results in RTT-like phenotypes in mice [RNA-seq]

Project description:Mutations in the MECP2 gene cause the profound neurological disorder Rett syndrome. MeCP2 protein is an epigenetic reader that recruits the NCOR1/2 corepressor complexes to methylated cytosine in its canonical CG setting, but also to methylated CA motifs, which are abundant in neurons but rare in other cell types. In this study we set out to test the biological significance of this non-canonical mode of DNA binding. To achieve this, we replaced the endogenous MeCP2 DNA binding domain with that of MBD2, which only binds mCG. Knock-in mice expressing the hybrid “MM2” protein created by this domain-swap displayed severe Rett syndrome-like phenotypes. This indicates that binding to mCA, specifically the mCAC trinucleotide, is critical for normal brain function and it offers a plausible explanation for the delayed onset of Rett syndrome, due to the coincident late accumulation of mCAC and its cognate interpreter, MeCP2. We show that the small subset of genes aberrantly expressed in both Mecp2-null and MM2 mice is strikingly enriched for genes implicated in neurological disorders, highlighting targets with potential relevance to the Rett syndrome phenotype

2021-02-07 | GSE152800 | GEO

Swapping the DNA binding domain of MeCP2 with that of MBD2 to abolish binding to non-CG methlyation results in RTT-like phenotypes in mice [ATAC-seq]

2021-02-07 | GSE151859 | GEO

Early-life gene expression in neurons modulates lasting epigenetic states. [Bisulfite-seq]

Project description:In mammals during the early postnatal period the environment plays a critical role in promoting the final steps in neuronal development. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here we show that in the brain during early life the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell type-specific transcription of genes that are critical for brain function.

2017-10-19 | GSE103213 | GEO

Early-life gene expression in neurons modulates lasting epigenetic states. [RNA-Seq]

2017-10-19 | GSE103185 | GEO

Early-life gene expression in neurons modulates lasting epigenetic states [ChIP-Seq]

2017-10-19 | GSE104578 | GEO

Early-life gene expression in neurons modulates lasting epigenetic states. [RNA-seq 2]

2017-10-19 | GSE104325 | GEO

Early-life gene expression in neurons modulates lasting epigenetic states. [Mnase-seq]

2017-10-19 | GSE104298 | GEO

Length-dependent gene misregulation in Rett syndrome (ChIP-seq)

Project description:Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that is proposed to function as a transcriptional repressor, but, despite numerous studies examining neuronal gene expression in MeCP2 mutants, no coherent model has emerged for how MeCP2 regulates transcription. Here we identify a genome-wide length-dependent increase in the expression of long genes in neurons lacking MeCP2. This gene misregulation occurs in human RTT brains and correlates with onset and severity of phenotypes in Mecp2 mutant mice, suggesting that the disruption of long gene expression contributes to RTT pathology. We present evidence that MeCP2 represses long genes by binding to brain-enriched, methylated CA dinucleotides within genes and show that loss of methylated CA in the brain recapitulates gene expression defects observed in MeCP2 mutants. We find that long genes encode proteins with neuronal functions, and overlap substantially with genes that have been implicated in autism and Fragile X syndrome. Reversing the overexpression of long genes in neurons lacking MeCP2 can improve some RTT-associated cellular deficits. These findings suggest that a function of MeCP2 in the mammalian brain is to temper the expression of genes in a length-dependent manner, and that mutations in MeCP2 and possibly other autism genes may cause neurological dysfunction by disrupting the expression of long genes in the brain. MeCP2 ChIP-seq from the forebrain and cerebellum of wild-type mice.

2015-03-12 | E-GEOD-60071 | biostudies-arrayexpress

Length-dependent gene misregulation in Rett syndrome (Bisulfite-seq)

2015-03-12 | E-GEOD-60062 | biostudies-arrayexpress

Length-dependent gene misregulation in Rett syndrome (Bisulfite-Seq 2)

2015-03-26 | GSE67292 | GEO