Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations
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ABSTRACT:
PROVIDER: PRJNA624265 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR11522389_1.fastq.gz | Fastqsanger.gz | |||
| SRR11522389_2.fastq.gz | Fastqsanger.gz | |||
| SRR11522390_1.fastq.gz | Fastqsanger.gz | |||
| SRR11522390_2.fastq.gz | Fastqsanger.gz | |||
| SRR11522391_1.fastq.gz | Fastqsanger.gz |
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Project description:Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations
2022-10-31 | GSE148435 | GEO
Project description:Rett syndrome is a neurodevelopmental disorder, caused by mutations in the MECP2 gene. Like other genetic disorders of neurodevelopment, it lacks molecular biomarkers to assess disease and therapy outcomes. We present a strategy to identify mechanisms of disease and biomarkers, which is reliant on a library of brain proteins defined by their responsiveness to Mecp2 gene dosage, and correlated with molecular, and clinical outcomes after AAV9-mediated MECP2 gene therapy into Mecp2-KO mouse brain. Gene rescue restored MECP2 brain expression, corrected clinical phenotypes in Mecp2-KO mice, and reverted transcriptome and proteome phenotypes. We identified 327 shared proteins among a total of 1852 proteins in cortex and hippocampus responsive to Mecp2/MECP2. Of these shared proteins, 119 have congruently expressed transcripts. Both the Mecp2-responsive proteome or the congruent 119 transcript-proteins pairs were enriched in synaptic and metabolic pathways including mitochondria carbon and NAD+ metabolism. We used this genetically validated and therapy-responsive library of proteins to inform the selection of putative biomarkers in cerebrospinal fluid of Rett patients. We analyzed cerebrospinal fluid composition of neurotypical and Rett subjects using an ultrasensitive nucleic acid based multiplexed ELISA. We identified 28 proteins altered in Rett patients, 9 of which overlapped with proteins sensitive to gene therapy and dosage. Multivariate regression linked several candidate biomarkers to Mecp2/MECP2 protein abundance and phenotypic improvements in mice. Our paradigm provides a rigorous molecular systems-level framework integrating genetics, preclinical MECP2 gene therapy, and rodent clinical metrics to define robust, cross-species biomarkers and mechanisms in Rett syndrome and other neurodevelopmental disorders.
2026-06-01 | GSE300536 | GEO
Project description:Rett syndrome is a neurodevelopmental disorder, caused by mutations in the MECP2 gene. Like other genetic disorders of neurodevelopment, it lacks molecular biomarkers to assess disease and therapy outcomes. We present a strategy to identify mechanisms of disease and biomarkers, which is reliant on a library of brain proteins defined by their responsiveness to Mecp2 gene dosage, and correlated with molecular, and clinical outcomes after AAV9-mediated MECP2 gene therapy into Mecp2-KO mouse brain. Gene rescue restored MECP2 brain expression, corrected clinical phenotypes in Mecp2-KO mice, and reverted transcriptome and proteome phenotypes. We identified 327 shared proteins among a total of 1852 proteins in cortex and hippocampus responsive to Mecp2/MECP2. Of these shared proteins, 119 have congruently expressed transcripts. Both the Mecp2-responsive proteome or the congruent 119 transcript-proteins pairs were enriched in synaptic and metabolic pathways including mitochondria carbon and NAD+ metabolism. We used this genetically validated and therapy-responsive library of proteins to inform the selection of putative biomarkers in cerebrospinal fluid of Rett patients. We analyzed cerebrospinal fluid composition of neurotypical and Rett subjects using an ultrasensitive nucleic acid based multiplexed ELISA. We identified 28 proteins altered in Rett patients, 9 of which overlapped with proteins sensitive to gene therapy and dosage. Multivariate regression linked several candidate biomarkers to Mecp2/MECP2 protein abundance and phenotypic improvements in mice. Our paradigm provides a rigorous molecular systems-level framework integrating genetics, preclinical MECP2 gene therapy, and rodent clinical metrics to define robust, cross-species biomarkers and mechanisms in Rett syndrome and other neurodevelopmental disorders.
2026-06-01 | GSE300534 | GEO
Project description:Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MECP2 mutations—a missense mutation (R306C) and a truncating mutation (V247X)—using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutations. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.
2026-06-18 | GSE318602 | GEO
Project description:Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MECP2 mutations—a missense mutation (R306C) and a truncating mutation (V247X)—using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutations. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.
2026-06-18 | GSE318601 | GEO
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
Project description:Mutations of the transcriptional regulator Mecp2 cause the X-linked autism spectrum disorder Rett syndrome (RTT), and Mecp2 has been implicated in several other neurodevelopmental disorders. To identify potential target genes regulated directly or indirectly by MeCP2, we performed comparative gene expression analysis via oligonucleotide microarrays on Mecp2-/y (Mecp2-null) and wild-type CPN purified via fluorescence-activated cell sorting (FACS).
2016-01-22 | GSE50225 | GEO
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
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.
2025-07-11 | GSE208056 | GEO
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