RNA Sequencing on hippocampal tissue after ASO treatment overtime in MECP2 duplication mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE151222 | GEO | 2022/05/26
REPOSITORIES: GEO
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Project description:RNA Sequencing on hippocampal tissue after ASO treatment overtime in MECP2 duplication mice
| PRJNA635145 | ENA
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71234 | GEO
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71233 | GEO
Project description:Our RNA-seq experiment (E-MTAB-5383) and subsequent in vitro analysis suggested that snoRD50a is a trans-acting RNA that can function in mRNA 3' processing. To test this hypothesis at transcriptomic level, we performed PAS-seq experiments to compare the polyA+ transcripts profile between negative control ASO (nc ASO) and snoRD50a ASO treated Hela cells, ASO (antisense oligonucletode) technique is a commonly used technique to deplete nuclear RNAs. snoRD50a ASO is used to deplete endogenous snoRD50a. See related experiments: E-MTAB-5383; E-MTAB-5384.
2017-05-31 | E-MTAB-5389 | biostudies-arrayexpress
Project description:Our RNA-seq experiment and subsequent in vitro analysis suggested that snoRD50a is a trans-acting RNA that can function in mRNA 3' processing. To test this hypothesis at transcriptomic level, we performed PAS-seq experiments to compare the polyA+ transcripts profile between negative control ASO (nc ASO) and snoRD50a ASO treated Hela cells
2017-07-01 | GSE98219 | GEO
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71229 | GEO
Project description:To identify potentially regulated target genes of MeCP2 we used celltype-specific models for transgenic overexpression and ablation of MeCP2. Gene expression was analyzed in cardiac biopsies of adult male mice. The study contains three different treatment groups: 1. healthy mice (Sham), 2. mice suffering from 4-6 weeks of cardiac pressure overload (TAC) and 3. with a reversible induction of TAC (TAC followed by 2 weeks without TAC)
2015-12-22 | GSE52796 | 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 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:MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXLS families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ CNV breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual’s clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (47%), terminal duplications (23%), inverted triplication structures (23%), and other CGRs (7%). A majority of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 67% of de novo events occurred in the terminal duplication group in contrast with 17% observed in tandem duplications. RNAseq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman = 0.63) between the log-transformed MECP2 RNA levels and MeCP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MeCP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: tandem duplications, other CGRs, terminal duplications/translocations, and triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MeCP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2024-08-12 | GSE256075 | GEO
Project description:We compared gene expression changes in the hypothalamus of mice lacking MeCP2 (Mecp2-null) and mice overexpressing MeCP2 (MECP2-transgenic). Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but surprisingly the majority of genes (~85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and repressor of transcription. Total hypothalamic RNA samples were collected from Mecp2-null male mice (n=4), MECP2-transgenic male mice (n=4), and their wild type male littermates at 6 weeks of age (n=4 for each group).
2008-05-30 | E-GEOD-11150 | biostudies-arrayexpress