Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA380103 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5366215.fastq.gz | Fastqsanger.gz | |||
| SRR5366216.fastq.gz | Fastqsanger.gz | |||
| SRR5366217.fastq.gz | Fastqsanger.gz | |||
| SRR5366218.fastq.gz | Fastqsanger.gz |
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Project description:Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia whereas rare variants have been found in patients with intellectual disability (ID), developmental disorders and autism spectrum disorder (ASD). Haploinsufficiency of TCF4 also causes Pitt Hopkins syndrome (PTHS); a condition characterized by developmental delay, ID and autonomic dysfunction. To understand the role of TCF4 in these disorders, we have used chromatin immunoprecipitation and next generation sequencing (ChIP-seq) to identify the genomic binding sites for TCF4. In this study we identify 10,604 binding sites assigned to 5,437 genes. De novo motif enrichment found that approximately 77% of the TCF4 binding sites contained at least one E-box (5’-CAtcTG). Furthermore, the majority of TCF4 binding sites overlapped with H3K27ac histone mark for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P < 5.3 x 10-7), ASD (P < 2.5 x 10-4) and ID (P < 7.6 x 10-3) were also enriched among TCF4 targets. These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include genetic risk factors for common neurodevelopmental disorders.
2017-12-08 | GSE96915 | GEO
Project description:The establishment of neural circuits depends on precise neuronal positioning in the cortex, a tightly coordinated process of neuronal differentiation, migration and terminal localization. Deficit in this process is implicated in several psychiatric disorders. Here, we show that the transcription factor Tcf4 controls neuronal positioning during brain development. Tcf4-deficient neurons become mispositioned in clusters when their migration to the cortical plate is complete. We reveal that Tcf4 regulates the expression of cell adhesion molecules to control neuronal positioning. Furthermore, through in vivo extracellular electrophysiology, we show that neuronal functions are disrupted after the loss of Tcf4. TCF4 mutations are strongly associated with schizophrenia and cause Pitt-Hopkins syndrome, which is characterized by severe intellectual disability. Thus, our results not only reveal the importance of neuronal positioning in brain development and but also provide new insights into the potential mechanisms underlying neurological defects linked to TCF4 mutations.
2021-09-20 | GSE166412 | GEO
Project description:The postsynaptic density (PSD) contains a collection of scaffold proteins used for the assembly of synaptic signaling complexes and disruption of this signaling machinery might be implicated in a variety of brain disorders. However, it is not known how the core-scaffold machinery associates this collection of proteins through development and how proteins coding for genes involved in psychiatric and other brain disorders are distributed through spatio-temporal protein complexes. Here, using immunopurification, proteomics, bioinformatics and mouse genetics, we isolated 2876 proteins across 41 in-vivo protein complexes and determined their protein domain composition, correlation to gene expression levels, and developmental integration to the PSD. We defined major protein clusters for enrichment of schizophrenia (SCZ), autism spectrum disorders (ASD), developmental delay (DD), and intellectual disability (ID) risk factors at embryonic day 14 and the adult PSD. These protein complexes contained a discrete number of protein domains defining molecular functions. Mutations in highly-connected nodes alter protein-protein interactions that modulate the assembly of macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform: Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of brain disease risk factors and their placement within synaptic protein interaction networks.
2017-08-22 | PXD006277 | Pride
Project description:BACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS: In order to explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. Effects on cell proliferation were assessed using high content imaging. RESULTS: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. CONCLUSIONS: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in Pitt-Hopkins Syndrome and risk for schizophrenia.
2016-10-01 | GSE62085 | GEO
Project description:Background: Autism spectrum disorder (ASD) is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for association of common variants with autism susceptibility risk has met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. Methods:M-BM- In this study, we utilized publically available GWAS data from the Autism Genome Project (AGP) and annotated the results (p < 0.001) for eQTLs present in the parietal lobe, cerebellum, and lymphoblastoid cell lines. We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency in order to generate an empirical p-value indicating statistically significant enrichment of eQTLs in top results from the autism GWAS. Results:M-BM- Our findings show a global enrichment of brain eQTLs, but not LCL eQTLs, among top SNPs from an autism GWAS. Additionally, the data implicates individual genesM-BM- SLC25A12,M-BM- PANX1M-BM- andM-BM- PANX2, as well as pathways previously implicated in autism. Conclusions:M-BM- These findings provide supportive rationale for the use of annotation-based approaches to GWAS. We use microarray technology to understand the etiology and pathology of psychiatric diseases at the transcriptomic level. Postmortem human brain samples came from the Stanley Medical Research InstituteM-bM-^@M-^Ys Neuropathology Consortium and Array collections, including schizophrenia, bipolar disorder and control samples.
2012-12-31 | E-GEOD-35974 | biostudies-arrayexpress
Project description:Background: Autism spectrum disorder (ASD) is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for association of common variants with autism susceptibility risk has met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum. Methods:M-BM- In this study, we utilized publically available GWAS data from the Autism Genome Project (AGP) and annotated the results (p < 0.001) for eQTLs present in the parietal lobe, cerebellum, and lymphoblastoid cell lines. We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency in order to generate an empirical p-value indicating statistically significant enrichment of eQTLs in top results from the autism GWAS. Results:M-BM- Our findings show a global enrichment of brain eQTLs, but not LCL eQTLs, among top SNPs from an autism GWAS. Additionally, the data implicates individual genesM-BM- SLC25A12,M-BM- PANX1M-BM- andM-BM- PANX2, as well as pathways previously implicated in autism. Conclusions:M-BM- These findings provide supportive rationale for the use of annotation-based approaches to GWAS. We use microarray technology to understand the etiology and pathology of psychiatric diseases at the transcriptomic level. Postmortem human brain samples came from the Stanley Medical Research InstituteM-bM-^@M-^Ys Neuropathology Consortium and Array collections, including schizophrenia, bipolar disorder and control samples.
2012-12-31 | E-GEOD-35977 | biostudies-arrayexpress
Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. Examination of TCF4 Isoform expression comparison between mutant and control skin fibroblast tissues
2016-05-31 | E-GEOD-77742 | 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:Genetic perturbations of the transcription factor, Forkhead Box P1 (FOXP1), occur in patients with autism spectrum disorder who have an increased risk for comorbidity with intellectual disability. Recent work has begun to reveal an important role for Foxp1 in brain development, but the brain region-specific contribution of Foxp1 to autism and intellectual disability phenotypes has yet to be fully determined. Here, we characterize Foxp1 conditional knockout (Foxp1cKO) mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are relevant to autism spectrum disorder, including hyperactivity, increased anxiety, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks that are relevant to intellectual disability. Using a genome-wide approach, we identified genes differentially expressed in the hippocampus of Foxp1cKO mice that are associated with synaptic function and physiology that could represent molecular networks related to the observed behavioral deficits. Finally, we observed reduced maintenance of long-term potentiation in the CA1 subfield of these animals. Together, these data suggest that expression of Foxp1 in pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors relevant to autism and intellectual disability. In particular, Foxp1 regulation of gene expression in the hippocampus appears to be crucial for normal CA1 physiology and spatial learning.
2018-02-13 | GSE97181 | GEO
Project description:SATB2, encoding a nuclear chromosomal scaffolding protein, is a schizophrenia risk gene and genetically associated with human intelligence. How SATB2 affects cognition at molecular level is currently unknown. Our data suggest that interactions between SATB2 and the inner nuclear membrane protein LEMD2 orchestrate gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology. We show that LEMD2, a candidate component of the A-heterochromatin tether, binds to SATB2 and the two proteins exert overlapping cellular functions. SATB2 is essential for neuronal activity-triggered nuclear envelope plasticity, which requires LEMD2 as well as the ESCRT-III/VPS4 complex. LEMD2-depletion in cortical neurons, like SATB2 ablation, affects the expression of multiple neuronal activity-regulated genes. The gene-sets regulated by LEMD2 and SATB2 significantly overlap and the LEMD2 gene-set is enriched for SATB2-bound genes. In human genetic data, LEMD2-regulated genes are enriched for loss-of-function mutations reported in autism, intellectual disability and schizophrenia and are, like SATB2-regulated genes, associated with cognitive function.
2020-11-29 | GSE157375 | GEO