MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130277 | GEO | 2019/08/27
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC6786283 | biostudies-literature
Project description:MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
| PRJNA534514 | ENA
Project description: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.
2016-12-01 | GSE90704 | GEO
Project description:The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with significantly modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.
2021-06-25 | GSE154111 | GEO
Project description:The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with significantly modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.
2021-06-25 | GSE124238 | GEO
Project description:The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with significantly modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.
2021-06-25 | GSE124240 | GEO
Project description:Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation c.353G>A, p.Gly118Glu (G118E) in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant causes the clinical symptoms and study its functional consequences, we established two disease models, including patient-derived iPSCs and a knock-in mouse line. Given that G118E mutation is in the DNA binding domain of MeCP2 and could potentially disrupt its chromatin association, we performed Cut&Run using WT and G118E mouse cortical tissue to characterize the genome wide binding pattern of WT and mutant MeCP2 proteins. We observed a reduction of DNA binding of G118E MeCP2 in the known MeCP2 target loci, as well as in a genome-wide manner.
2023-11-13 | GSE243009 | GEO
Project description:The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with significantly modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.
2021-06-25 | GSE124239 | GEO
Project description:The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with significantly modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.
2021-06-25 | GSE124236 | GEO
Project description:Rett syndrome (RTT) is one of the most prevalent female mental disorders. De novo mutations in methyl CpG binding protein 2 (MeCP2) are a major cause of RTT. MeCP2 regulates gene expression as a transcription regulator as well as through long-range chromatin interaction. Because MeCP2 is present on the X chromosome, RTT is manifested in a X-linked dominant manner. Investigation using murine MeCP2 null models and post-mortem human brain tissues has contributed to understanding the molecular and physiological function of MeCP2. In addition, RTT models using human induced pluripotent stem cells derived from RTT patients (RTT-iPSCs) provide novel resources to elucidate the regulatory mechanism of MeCP2. Previously, we obtained clones of female RTT-iPSCs that express either wild type or mutant MECP2 due to the inactivation of one X chromosome. Reactivation of the X chromosome also allowed us to have RTT-iPSCs that express both wild type and mutant MECP2. Using these unique pluripotent stem cells, we investigated the regulation of gene expression by MeCP2 in pluripotent stem cells by transcriptome analysis. We found that MeCP2 regulates genes encoding mitochondrial membrane proteins. In addition, loss of function in MeCP2 results in de-repression of genes on the inactive X chromosome. Furthermore, we showed that each mutation in MECP2 affects a partly different set of genes. These studies suggest that fundamental cellular physiology is affected by mutations in MECP2 from very early fetal development and that a therapeutic approach targeting to unique forms of mutant MeCP2 is needed. RNA samples from normal ESCs/iPSCs, RTT-iPSCs and MeCP2 KD iPSCs were obtained. Gene expression of those cells were analyzed.
2013-10-25 | E-GEOD-51607 | biostudies-arrayexpress