Random mono-allelic expression in MECP2-mutated cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE140740 | GEO | 2019/11/21
REPOSITORIES: GEO
Similar Datasets
Project description:Random mono-allelic expression in MECP2-mutated cells
| PRJNA590731 | ENA
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.
2023-09-01 | GSE214547 | 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. Evaluation of off-target effects of dCpf1-CTCF with crRNA targeting CTCF binding flanking MECP2 locus
2023-09-01 | GSE214548 | 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
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.
2013-10-25 | GSE51607 | GEO
Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. RTT is characterized by having apparently normal development until 6-18 months, when a progressive decline in motor and language functions begins and breathing abnormalities and seizures present. Here we present the first proteomic analysis in a RTT mouse model. Examining whole cortex tissue in symptomatic males (Mecp2Jae/y) and wild-type littermates, we have identified 465 proteins significantly altered. Pathway analysis identified biological pathways ubiquitous to multiple cell types as well as cell type specific pathways, underscoring the contributions of multiple central nervous system (CNS) cell populations to the disease pathogenesis.
2017-11-02 | PXD006460 | Pride
Project description:We compared gene expression changes in the cerebellum of mice lacking MeCP2 (Mecp2-null) and mice overexpressing MeCP2 (MECP2-transgenic). A group of postnatal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Keywords: Comparison of cerebellar gene expression data between Mecp2-null mice and Mecp2-transgenic mice Total cerebellar RNA samples were collected from Mecp2-null male mice (n=5), MECP2-transgenic male mice (n=5), and their wild type male littermates at 6 weeks of age (n=5 for each group).
2010-04-10 | E-GEOD-15574 | biostudies-arrayexpress
Project description:Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix (HLH) genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT. Keywords: Neuronal Differentiation, Targets of MeCP2, Rett syndrome.
2006-06-15 | GSE4600 | GEO
Project description:We compared gene expression changes in the cerebellum of mice lacking MeCP2 (Mecp2-null) and mice overexpressing MeCP2 (MECP2-transgenic). A group of postnatal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Keywords: Comparison of cerebellar gene expression data between Mecp2-null mice and Mecp2-transgenic mice
2009-04-07 | GSE15574 | GEO