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Dynamic dysregulation of the transcriptome upon deletion of Mecp2 in adult mice [CUT&RUN]

ABSTRACT: Loss of function mutations in methyl Cpg binding protein 2 (MECP2) cause Rett syndrome. Loss of MeCP2 causes global transcriptional dysregulation, but it was unknown whether this transcriptional dysregulation was proximal to Mecp2 function. We deleted Mecp2 from adult mice and performed a time-series CUT&RUN experiment to identify if MeCP2 binding or histone post-translational modficiations are altered immediately upon loss of MeCP2.

ORGANISM(S): Mus musculus

PROVIDER: GSE246664 | GEO | 2024/12/16

REPOSITORIES: GEO

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Dynamic dysregulation of the transcriptome upon deletion of Mecp2 in adult mice

Project description:Loss of function mutations in methyl Cpg binding protein 2 (MECP2) cause Rett syndrome. Loss of MeCP2 causes global transcriptional dysregulation, but it was unknown whether this transcriptional dysregulation was proximal to Mecp2 function. We deleted Mecp2 from adult mice and performed a time-series RNA-seq experiment to identif what transcripts were altered immediately upon loss of MeCP2.

2024-12-16 | GSE246119 | GEO

Transcriptional dysregulation in a Mecp2 methyl-binding domain point mutant model (Mecp2 G118E)

Project description:We recently identified a mutation in the methyl-binding domain of MECP2 (MECP2 G118E) in a male patient with Rett syndrome. To ask whether this mutation conferred similar molecular dysregulation as observed in previous mouse models of Rett syndrome, we generated a knockin mouse model of this mutation and collected the cortex for RNA-sequencing.

2024-12-16 | GSE277077 | GEO

MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation

Project description:Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. Theepigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shownpreviously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatinreorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mousebrain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, whichlead to minor changes in either heterochromatin binding kinetics or clustering. We found that MeCP2 is (di)methylated on severalarginines and that this modification alters heterochromatin organization. Interestingly, we identified the Rett syndrome mutationsite R106 as a dimethylation site. In addition, co-expression of protein arginine methyltransferases 1 and 6 lead to a decrease ofheterochromatin clustering. Altogether, we identified and validated novel modifications of MeCP2 in the brain and show that thesecan modulate its ability to bind as well as reorganize heterochromatin, which may play a role in the pathology of Rett syndrome.

2022-10-15 | PXD033696 | Pride

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

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

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

2021-06-25 | GSE124240 | GEO

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion

2021-06-25 | GSE124238 | GEO

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion [ChIP-seq]

2021-06-25 | GSE124236 | GEO

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion [RNA-seq]

2021-06-25 | GSE124239 | GEO

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion [Flag-HA ChIP-seq]

2021-06-25 | GSE124237 | GEO

Transcriptome analysis of a MECP2 conditional KO mouse model

Project description:Rett syndrome is a severe neurodevelopmental condition that rsults primarily from mutations in the MECP2 gene. MECP2 is known to function as both a transcriptional activator and transcriptional repressor. However, it remains unclear how transcriptional dysregulation resulting from MECP2 mutations lead to the Rett syndrome phenotype. Multiple mouse models have been generated to investigate the function of MECP2 in vivo. Remarkably, despite the neurodevelopmental phenotype characteristic of Rett syndrome, temporal conditional MECP2 knock-out mouse models with MECP2 deletion induced postnatally recapitulate the Rett-syndrome-like phenotype in mouse. Here we investigated gene expression changes in 22-weeks old mice following conditional MECP knock-out at 12 weeks by RNA-sequencing. Consistent with previous data, we identify mild gene expression changes following MECP2 knock-out. These data could prove valuable in future studies comparing conditional MECP2 knock-out at distinct time points and in additional brain regions, and can also serve for investigating alternative splicing changes resulting from MECP2 conditional deletion.

2018-04-05 | GSE112663 | GEO

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