MeCP2 Represses the Activity of Topoisomerase IIb in Long Neuronal Genes [eTIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA832576 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:MeCP2 Represses the Activity of Topoisomerase IIb in Long Neuronal Genes
| PRJNA1032965 | ENA
Project description:MeCP2 Represses the Activity of Topoisomerase IIb in Long Neuronal Genes [ChIP-Seq]
| PRJNA1032966 | ENA
Project description:MeCP2 Represses the Activity of Topoisomerase IIb in Long Neuronal Genes [RNA-Seq]
| PRJNA1032967 | ENA
Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2b) in neurons. We show that MeCP2 and TOP2b physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2b activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2b activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2b at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
2023-11-11 | GSE246461 | GEO
Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2b) in neurons. We show that MeCP2 and TOP2b physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2b activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2b activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2b at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
2023-11-11 | GSE246460 | GEO
Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2b) in neurons. We show that MeCP2 and TOP2b physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2b activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2b activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2b at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
2023-11-11 | GSE201658 | GEO
Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2β) in neurons. We show that MeCP2 and TOP2β physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2β activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2β activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2β at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
2023-11-15 | PXD046904 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-11 | GSE246463 | 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