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Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

ABSTRACT: Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

PROVIDER: PRJNA515413 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8447240_1.fastq.gz	Fastqsanger.gz
	SRR8447240_2.fastq.gz	Fastqsanger.gz
	SRR8447231_1.fastq.gz	Fastqsanger.gz
	SRR8447231_2.fastq.gz	Fastqsanger.gz
	SRR8447241_1.fastq.gz	Fastqsanger.gz

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Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

Project description:Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

2020-01-01 | GSE125155 | GEO

Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome.

| S-EPMC7117907 | biostudies-literature

Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome

Project description:This SuperSeries is composed of the following subset Series: GSE24285: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (mm8 chromosomal tiling arrays) GSE24286: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (mm8 promoter tiling arrays) GSE24320: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (high-throughput small RNA sequencing) Refer to individual Series

2010-09-29 | E-GEOD-24329 | biostudies-arrayexpress

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

Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (WGBS)

Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of MECP2. Reactivation of the silent wild-type MECP2 allele on the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female RTT patients. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 on Xi. Demethylation of the MECP2 promoter by dCas9-Tet1 with target sgRNA reactivated MECP2 on Xi in RTT hESCs without detectable off-target effects at the transcriptome level. Neurons derived from methylation edited RTT hESCs reversed the smaller soma size and electrophysiological abnormalities. Insulation of the methylation edited MECP2 locus in RTT neurons by dCpf1-CTCF with target crRNA stabilized MECP2 reactivation and rescued the RTT-related neuronal defects, providing a proof-of-concept study for multiplex epigenome editing to treat RTT.

2023-09-01 | GSE214549 | GEO

Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

Project description:Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

2022-10-31 | GSE148435 | GEO

Length-dependent gene misregulation in Rett syndrome (MeCP2)

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.

2015-03-12 | GSE60074 | GEO

Transcription profiling of human super frontal gyrus (post mortem brain) from Rett syndrome patients and age sex matched controls reveals FXYD1, an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice

Project description:Rett syndrome (RTT, OMIM 312750) is a severe X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. The disorder is almost exclusively diagnosed in females, because males affected by the disease usually die perinatally due to severe encephalopathy. Direct MeCP2 target genes underlying the neuropathogenesis of RTT remain largely unknown.

2007-11-02 | E-GEOD-6955 | biostudies-arrayexpress

Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (ChIP-Seq)

2023-09-01 | GSE214547 | GEO

Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (RNA-Seq)

2023-09-01 | GSE214548 | GEO