Domains of methylated CAC and CG target MeCP2 to tune transcription in the brain
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA330796 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3929460_1.fastq.gz | Fastqsanger.gz | |||
| SRR3929460_2.fastq.gz | Fastqsanger.gz | |||
| SRR3929660_1.fastq.gz | Fastqsanger.gz | |||
| SRR3929660_2.fastq.gz | Fastqsanger.gz | |||
| SRR3929661_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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
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 | GSE123371 | GEO
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 | GSE123372 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-05-04 | GSE84671 | GEO
Project description:Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation.
2019-11-26 | GSE139510 | GEO
Project description:Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. Using multiple approaches, we demonstrate that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation in the brain directly, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which it binds broadly across highly methylated regions of DNA, but acts from a distance to attenuate transcriptional initiation.
2019-11-26 | GSE128185 | GEO
Project description:To evaluate the effect of CG methylation on DNA binding of sequence-specific B-ZIP transcription factors (TFs) in a high-throughput manner, we enzymatically methylated the cytosine in the CG dinucleotide on protein binding microarrays. Two Agilent DNA array designs were used. One contained 40,000 features using de Bruijn sequences where each 8-mer occurs 32 times in various positions in the DNA sequence. The second contained 180,000 features with each CG containing 8-mer present three times. The first design was better for identification of binding motifs, while the second was better for quantification. Using this novel technology, we show that CG methylation enhanced binding for CEBPA and CEBPB and inhibited binding for CREB, ATF4, JUN, JUND, CEBPD and CEBPG. The CEBPB|ATF4 heterodimer bound a novel motif CGAT|GCAA 10-fold better when methylated. EMSA confirmed these results. CEBPB ChIP-seq data using primary female mouse dermal fibroblasts with 50X methylome coverage for each strand indicate that the methylated sequences well-bound on the arrays are also bound in vivo. CEBPB bound 39% of the methylated canonical 10-mers ATTGC|GCAAT in the mouse genome. After ATF4 protein induction by thapsigargin which results in ER stress, CEBPB binds methylated CGAT|GCAA in vivo, recapitulating what was observed on the arrays. This methodology can be used to identify new methylated DNA sequences preferentially bound by TF, which may be functional in vivo. To evaluate the effect of CG methylation on DNA binding of sequence-specific B-ZIP transcription factors (TFs) in a high-throughput manner, we enzymatically methylated the cytosine in the CG dinucleotide on protein binding microarrays. Two Agilent DNA array designs were used. One contained 40,000 features using de Bruijn sequences where each 8-mer occurs 32 times in various positions in the DNA sequence. The second contained 180,000 features with each CG containing 8-mer present three times. The first design was better for identification of binding motifs, while the second was better for quantification. Using this novel technology, we show that CG methylation enhanced binding for CEBPA and CEBPB and inhibited binding for CREB, ATF4, JUN, JUND, CEBPD and CEBPG. The CEBPB|ATF4 heterodimer bound a novel motif CGAT|GCAA 10-fold better when methylated. EMSA confirmed these results. CEBPB ChIP-seq data using primary female mouse dermal fibroblasts with 50X methylome coverage for each strand indicate that the methylated sequences well-bound on the arrays are also bound in vivo. CEBPB bound 39% of the methylated canonical 10-mers ATTGC|GCAAT in the mouse genome. After ATF4 protein induction by thapsigargin which results in ER stress, CEBPB binds methylated CGAT|GCAA in vivo, recapitulating what was observed on the arrays. This methodology can be used to identify new methylated DNA sequences preferentially bound by TF, which may be functional in vivo. Protein binding microarray (PBM) experiments were performed for a set of 8 mouse B-ZIP homodimers and one hetrodimer transcription factors. Briefly, the PBMs involved binding GST-tagged DNA-binding proteins to double-stranded and methylated or unmethylated 44K Agilent microarrays, containing a DeBruijn sequence design, in order to determine their sequence preferences. Details of the PBM protocol are described in Berger et al., Nature Biotechnology 2006.
2013-02-15 | E-GEOD-44338 | biostudies-arrayexpress
Project description:Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation.
2019-11-26 | GSE139509 | GEO
Project description:Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation.
2019-11-26 | GSE139508 | GEO
Project description:Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome, and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. Using multiple approaches, we demonstrate that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation in the brain directly, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which it binds broadly across highly methylated regions of DNA, but acts from a distance to attenuate transcriptional initiation.
2019-11-26 | GSE128183 | GEO