Transcriptional consequences of manipulating the candidate schizophrenia susceptibility gene miR-137 in human neural progenitor cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49793 | GEO | 2014/02/10
SECONDARY ACCESSION(S): PRJNA214942
REPOSITORIES: GEO
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Project description:In the largest published genome-wide association study (GWAS) of schizophrenia to date (PGC1), the most significant association (P = 1.6 X 10-11) was observed at an intronic variant (rs1625579) within the MIR137 host gene (MIR137HG). In this study we have performed genome-wide RNA profiling of a human foetal neural progenitor cell line following miR-137 manipulation, in order to identify gene expression changes through which genetic variation at the MIR137HG locus could confer susceptibility to schizophrenia. Total RNA extracted from human neural progenitor cells manipulated with either mir137 inhibitor or mimic. 4 replicates per group. Genome wide transcript levels were then measured using gene expression microarrays.
2014-02-10 | E-GEOD-49793 | biostudies-arrayexpress
Project description:MicroRNAs have been implicated in the pathology not only of cancer, but also of psychiatric diseases, such as bipolar disorder and schizophrenia. As several psychiatric disorders share the same risk genes, we hypothesized that this microRNA could also be associated with attention-deficit/hyperactivity disorder (ADHD) and that this association to psychiatric disorders might be due to the variable number of tandem repeats (VNTR) polymorphism within the internal miR-137 (Imir137) promoter (PMID 18316599; PMID 25154622). To further understand the role of the microRNA 137 in the brain a knock-down of miR-137 expression in SH-SY5Y neuroblastoma cells was performed followed by expression analysis using a microarray.
2018-12-01 | GSE66433 | GEO
Project description:Genome-wide association studies indicate allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. As a result, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA. However, there remains a gap in using LNPs to regulate gene and protein expression in the brain. To study the delivery of nucleic acids by LNPs to the brain, we found that LNPs released miR137 cargo and inhibited synaptic target transcripts in neuronal cultures. Biodistribution of LNPs loaded with firefly luciferase mRNA remained localized to the mouse prefrontal cortex (PFC) injection site without circulating to off-target organs. LNPs encapsulating Cre mRNA preferentially co-expressed in neuronal over microglial or astrocytic cells. Using quantitative proteomics, we found miR137 modulated glutamatergic synaptic protein networks that are commonly dysregulated in SCZ. These studies support engineering the next generation of brain-specific LNPs to deliver personalized RNA therapeutics and improve symptoms of central nervous system disorders.
2023-09-05 | PXD041648 | Pride
Project description:Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline (gKO) or nervous system (cKO) leads to postnatal lethality, while heterozygous gKO and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.
2018-10-09 | GSE79661 | GEO
Project description:Recent genetic evidence has revealed microRNA-137 (miR-137) as a risk gene in schizophrenia and autism spectrum disorder (ASD), and the following cellular studies have demonstrated the importance of miR-137 in regulating neurogenesis. We have generated miR-137 knockout mice which display behaviors that resemble some symptoms of these two diseases. To investigate the underlying molecular mechanism, we performed comprehensive analyses of the entire RNA and protein molecules of the miR-137 mouse brains. The dataset uploaded here is the raw data of the mass spectrometry-based whole proteome analysis of the six miR-137 mouse brains: wild-type, heterozygous (miR-137+/–) and homozygous (miR-137–/–) from two different litters. The tandem mass tag (TMT) methodology was employed in this proteomics analysis for the quantitation. The sample channels are: 128C (miR-137+/+, litter 1), 129N (miR-137+/–, litter 1), 129C (miR-137–/–, litter 1), 130N (miR-137+/+, litter 2), 130C (miR-137+/–, litter 2), and 131N (miR-137–/–, litter 2).
2018-10-17 | PXD003874 | Pride
Project description:miR-137 plays critical roles in the nervous system and tumor development. An increase in its expression is required for neuronal differentiation while its reduction is implicated in gliomagenesis. To evaluate the potential of miR-137 in glioblastoma therapy, we conducted genome-wide target mapping in glioblastoma cells by measuring levels of associations between PABP and mRNAs in cells transfected with miR-137 mimics vs. controls via RIPSeq. Impact on mRNA levels was also measured by RNASeq. By combining the results of both experimental approaches, 1468 genes were determined to be negatively impacted by miR-137; among them, 595 (40%) contain miR-137 predicted sites. The most relevant targets include oncogenic proteins and players in neurogenesis like c-KIT, YBX1, AKT2, CDC42, CDK6 and TGFβ2. Interestingly, we observed that several identified miR-137 targets are also predicted to be regulated by miR-124, miR-128 and miR-7, which are equally implicated in neuronal differentiation and gliomagenesis. We suggest that the concomitant increase of these four miRNAs in neuronal stem cells or their repression in tumor cells could produce a robust regulatory effect with major consequences to neuronal differentiation and tumorigenesis. Identification of genes affected by miR137 transfection via RIP-Seq and RNA-Seq in U251 and U343 cells
2014-02-11 | E-GEOD-53220 | biostudies-arrayexpress
Project description:Schizophrenia is a severe psychiatric illness that affects ~1% of the population and has a strong genetic underpinning. Recently, genome wide analysis of copy number variation (CNV) has implicated rare and de novo events as important in schizophrenia. Here we report a genome-wide analysis of 245 schizophrenia cases and 490 controls, all of Ashkenazi Jewish descent. Since many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, as increasing evidence suggests an overlap of specific rare CNVs between autism and schizophrenia. By combining our data with prior CNV studies of schizophrenia and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7,545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with schizophrenia (p = 0.02) and an odds ratio estimate of 17 (95% CI: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior schizophrenia family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for schizophrenia susceptibility. Copy Number alanysis was performed on 245 cases and 490 controls of Ashkenazi Jewish descent. Samples were analyzed for deletions greater than 500 kb, with 20 or more snps in the interval. Three algorithms were used for analysis, GADA, GLAD and BEAST. The reference was created by using all samples processed here as the reference.
2010-08-06 | E-GEOD-23201 | biostudies-arrayexpress
Project description:Schizophrenia is a severe psychiatric illness that affects ~1% of the population and has a strong genetic underpinning. Recently, genome wide analysis of copy number variation (CNV) has implicated rare and de novo events as important in schizophrenia. Here we report a genome-wide analysis of 245 schizophrenia cases and 490 controls, all of Ashkenazi Jewish descent. Since many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3–1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, as increasing evidence suggests an overlap of specific rare CNVs between autism and schizophrenia. By combining our data with prior CNV studies of schizophrenia and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7,545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with schizophrenia (p = 0.02) and an odds ratio estimate of 17 (95% CI: 1.36–1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior schizophrenia family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for schizophrenia susceptibility.
2010-08-06 | GSE23201 | GEO
Project description:Genome-wide association study (GWAS) was performed in 120 patient-parents trio samples from Japanese schizophrenia pedigrees ABSTRACT: Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p < 0.01 and 473 SNPs of p < 0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. SUPPLEMENTARY FILES: CEL files were processed by manufacture's protocol. Genotype data were analyzed with the GeneSpring GT (Varia) 2.0 software package developed by Agilent Technologies (Santa Clara, CA). Matrix tables for the Genetic programs were produced (Linkage format: http://bioinformatics.med.utah.edu/~alun/software/docs/linkage.html) File 1: Matrix file_SNP_Map.txt File 2: Matrix file_Family_Information.txt File 3: Matrix file_Pedigree_Format.txt (Genotyping data of Linkage format) Transmission disequilibrium test was performed using the R program (http://www.r-project.org). File 4: Matrix file_results.txt
2011-06-13 | E-GEOD-27923 | biostudies-arrayexpress
Project description:Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately one percent of the general population. Most genetic studies so far focused on disease association with common genetic variation such as single nucleotide polymorphisms, but recently it has become apparent that large-scale genomic copy number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrixâ GeneChip 250K SNP arrays. Keywords: genomic hybridisation We hybridized genomic DNA of 54 patients with deficit schizophrenia to Affymetrix' GeneChip 250K SNP (Nsp) arrays, and identified genome-wide CNV using the Copy Number Analyzer for Affymetrix GeneChip (CNAG v2.0) software, which uses a Hidden Markov Model (HMM) algorithm to calculate copy numbers.
2010-05-18 | E-GEOD-12714 | biostudies-arrayexpress