Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE117248 | GEO | 2020/05/24
REPOSITORIES: GEO
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Project description:Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Here we describe the establishment of an isogenic human pluripotent embryonic stem cell model of FXS. Using CRISPR/Cas9 to introduce indels in exon 3 of FMR1 and result in complete loss of FMRP (FMR1KO). We show that FMRP-deficient neurons exhibit a number of phenotypic abnormalities including neurite outgrowth and branching deficits and impaired electrophysiological network activity as measured by multi-electrode arrays. RNA-Seq analysis of FMRP-deficient neurons revealed transcriptional dysregulation in pathways related to neurodevelopment, neurotransmission, and the cell cycle
2020-06-09 | PXD011445 | Pride
Project description:Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Here we describe the establishment of an isogenic human pluripotent embryonic stem cell model of FXS. Using CRISPR/Cas9 to introduce indels in exon 3 of FMR1 and result in complete loss of FMRP (FMR1KO). We show that FMRP-deficient neurons exhibit a number of phenotypic abnormalities including neurite outgrowth and branching deficits and impaired electrophysiological network activity as measured by multi-electrode arrays. RNA-Seq and proteome analysis of FMRP-deficient neurons revealed transcriptional dysregulation in pathways related to neurodevelopment, neurotransmission, and the cell cycle.
2020-06-18 | PXD011630 | Pride
Project description:Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome
| PRJNA481532 | ENA
Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
2023-06-08 | PXD040331 | Pride
Project description:Fragile X syndrome (FXS) is caused by the absence of the fragile X mental retardation protein (FMRP). We have previously generated FXS-induced pluripotent stem cells (iPSCs) from patients' fibroblasts. In this study, we aimed at unraveling the molecular phenotype of the disease. Our data revealed aberrant regulation of neural differentiation and axon guidance genes in FXS-derived neurons, which are regulated by the RE-1 silencing transcription factor (REST). Moreover, we found REST to be elevated in FXS-derived neurons. As FMRP is involved in the microRNA (miRNA) pathway we employed microRNA-array analyses and uncovered several miRNAs dysregulated in FXS-derived neurons. We found hsa-mir-382 to be down-regulated in FXS-derived neurons, and introduction of mimic-mir-382 into these neurons was sufficient to repress REST and up-regulate its axon guidance target genes. Our data link, FMRP and REST, through the miRNA pathway, and show a new aspect in the development of FXS. Affimetrix miRNA array of two WT and two fragile X syndrome derived neurons
2014-10-28 | E-GEOD-62721 | biostudies-arrayexpress
Project description:Fragile X syndrome (FXS) is a neurodevelopmental disorder and a leading cause of intellectual disability. In FXS, the neuronal regulator, FMR1, is epigenetically silenced by a CGG repeat expansion. Here, we investigate conditions under which repeat expansion and gene silencing could be reversed. Surprisingly, inducing formation of R-loops (3-stranded RNA-DNA structures) within FMR1 is sufficient to initiate CGG contraction, promoter demethylation, and FMR1 reactivation. Recruiting RNaseH degrades the R-loop and abolishes the response. Targeting the nascent mRNA for degradation also eliminates the response. Thus, we have identified an exogenous nuclease-free method of contracting CGG repeats and reversing FMR1 silencing. We propose that DNA demethylation, new transcription, and R-loop formation engage in a feed-forward cycle to contract CGG repeats and reactivate FMR1.
2023-05-19 | GSE184580 | GEO
Project description:ene pleiotropy defines the capacity of a gene to impact multiple phenotypic characters. The Fragile X Mental Retardation 1 (FMR1) gene is a candidate for pleiotropy, as it controls protein synthesis through its product, the translational regulator FMRP. As FMR1 loss-of-function leads to neurodevelopmental defects and Fragile X Syndrome (FXS), intellectual disability and autism, FMR1 functions have been mostly studied in the brain. FMR1-deficiency could also have yet unexplored consequences in periphery and impact metabolism through translational repression in peripheral organs. We combined 1H NMR-based metabolic phenotyping and proteomics to reveal the pleiotropic metabolic effects associated with FMR1-deficiency in mouse and human. We demonstrate that Fmr1-deficiency in the mouse increases hepatic translation, improves glucose tolerance and insulin sensitivity and reduces adiposity, while enhancing -adrenergic driven lipolysis and utilization of lipid energetic substrates. Last, we provide converging evidences in FXS patients that the levels of glucose, insulin and free fatty acids are modified, suggesting that FMR1-deficiency also drives metabolic readjustments in human. As part of a larger study investigating the involvement of fmr in metabolic alteration in fmr1-KO mice, fmr1-KO mouse livers were analysed by MS.
2022-02-28 | PXD007241 | Pride
Project description:Fragile X syndrome (FXS) is one of the most prevalent inherited intellectual disabilities. The patients carry the expansion of over 200 CGG repeats located at the 5′ untranslated region of fragile X mental retardation 1 (FMR1). As a result, the FMR1 promoter becomes hypermethylated leading to decreased or absent expression of its encoded RNA-binding protein fragile X mental retardation protein (FMRP). We previously generated human induced pluripotent stem (iPS) cells from fibroblasts of a FXS patient (FXS-iPSC) with expanded CGG-repeats at the FMR1 promoter. In the present work, we explored the transcriptional misregulation during the embryonic neurogenesis by in-vitro differentiation of FXS-iPSC into neurons through the intermediate stages. At each differentiation stage, we collected RNA and performed RNA-seq. After an integrated analysis, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. Furthermore, we found the cholesterol synthesis genes (e.g., SQLE, LSS, and FASN) are up-regulated during the in-vitro neuronal differentiation of FXS-iPSC, which may contribute to the obesity phenotype of FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, and also discovered many potential candidate genes for the cure of FXS symptoms such as neuronal abnormalities and obesity.
2016-03-04 | GSE76490 | GEO
Project description:Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is caused by an expansion of CGG repeats located in the 5Õ untranslated region (UTR) of the FMR1 gene, leading to hypermethylation and silencing of this locus. While the dramatic increase in DNA methylation (DNAm) of the FMR1 full mutation allele is well documented, the extent that these changes affect DNAm throughout the entire gene and the rest of the genome remains unexplored. Here, we examine the genome-wide methylation in peripheral blood (N = 9) as well as induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls (N = 53 and 9, respectively) and find the expected significant DNAm differences in the FMR1 promoter and 5Õ UTR, but also that these changes inversely persist throughout the FMR1 gene body. Importantly, we find there are no additional differential methylated loci (DML) throughout the remainder of the genome, indicating that the aberrant methylation of the FMR1 in FXS is locus-specific and does not change DNAm genome-wide. This study provides a comprehensive methylation profile of FXS and refines mechanistic considerations of FMR1 silencing. A total of 62 blood (53 controls + 9 Fragile X) samples analyzed using a linear regression model.
2013-04-15 | E-GEOD-41273 | biostudies-arrayexpress
Project description:Fragile X syndrome (FXS), the most common genetic form of intellectual disability in male, is caused by the silence of FMR1. Hypermethylation of the CGG expansion mutation in the 5’UTR region of FMR1 in FXS patients was thought to epigenetically silence FMR1. Here, we applied our previously developed DNA methylation editing tool to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/gRNA switched the heterochromatin status of the FMR1 promoter to an active chromatin status and subsequently restored FMR1 expression in FXS iPSCs. Neurons derived from methylation edited FXS iPSCs showed a similar electrophysiological property as wild-type neurons, and maintained FMR1 expression for months after engrafting into the mouse brain. Reactivation of FMR1 can be achieved in FXS neurons with demethylation of the CGG expansion. Lastly, we showed that targeted demethylation of the FMR1 promoter can reactivate FMR1 as well suggesting potential therapeutic approaches for FXS.
2018-02-16 | GSE102655 | GEO