Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96915 | GEO | 2017/12/08

SECONDARY ACCESSION(S): PRJNA380103

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptomic signatures of risk genes implicated in psychiatric disorders during neuronal differentiation

Project description:Susceptibility genes for Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), monogenetic disorders with intellectual disabilities (ID) or schizophrenia (SCZ) converge on processes related to neuronal function and differentiation. Furthermore, ASD risk genes are enriched for FMRP (Fragile X Mental Retardation Protein) targets and for genes implicated in ID. In addition, a significant co-heritability was observed between ASD and SCZ. The genetic overlap between ASD, FXS, ID and SCZ together with the symptomatic differences gives rise to the question if pathomechanisms impair the same or different regulatory patterns activated during neuronal differentiation (ND). To test this idea, we performed transcriptome analysis of in-vitro differentiation of the neuroblastoma cell line model SH-SY5Y and identified genes that were differentially expressed, dynamically regulated, and coordinately expressed. The identified genetic modules activated during ND are enriched for genetic risk factors for these four disorders. Although risk genes for the disorders significantly overlap, we observed disorder specific enrichments: ASD or FXS implicated genes were likely to be positive regulators of ND whereas ID implicated genes were related to negative regulation. ASD and SCZ genes were specifically enriched among cholesterol and fatty acid associated modules. ID genes were overrepresented among cell cycle modules. In addition, we show that ASD genes are likely to be hub genes. We hypothesize that knowledge about genetic variants of an individual combined with network and pathway context of the related genes will allow differentiating between psychiatric disorders. 21 samples, consisting of 3 replicates harvested at 7 different time-points of RA+BDNF-induced neuronal differentiation

2016-06-01 | E-GEOD-69838 | biostudies-arrayexpress

Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders

Project description:Based on a transcriptomic and functional approach, we performed ex-vivo studies on fibroblasts originated from a patient with Intellectual Disability and Autism Spectrum Disorders (ID-ASD) carrying a nonsense de novo mutation in CSDE1. The aim is to decipher the CSDE1-dependent biological pathways involved in the pathophysiology of ID-ASD. We identified the Wnt/β-catenin pathway and cell adhesion as two deregulated cellular pathways deregulated in the ID-ASD patient.

2023-12-09 | GSE162954 | GEO

Transcriptomic signatures of risk genes implicated in psychiatric disorders during neuronal differentiation

2016-06-01 | GSE69838 | GEO

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress

Building a schizophrenia genetic network: Transcription Factor 4 regulates genes involved in neuronal development and schizophrenia risk

Project description:The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10-5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.

2018-04-05 | GSE112704 | GEO

Transcriptome of iPSC-derived Cerebral Organoids with Heterozygous Knockout in CHD8

Project description:CHD8 (chromodomain helicase DNA binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is the most commonly mutated gene in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities, and affects cancer cell proliferation. To better understanding the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout (KO) one copy of CHD8 in induced pluripotent stem cells (iPSCs) and build cerebral organoids, a model for the developing telencephalon. RNA-seq was carried out on KO organoids (CHD8+/-) and isogenic controls (CHD8+/+). Differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, forebrain development, Wnt/β-catenin signaling and axonal guidance. The SZ and bipolar disorder (BD) candidate gene TCF4 was significantly upregulated. Our CHD8 KO DEGs were significantly overlapped with those found in a transcriptome analysis using cerebral organoids derived from a family with idiopathic ASD and another transcriptome study using iPS cell-derived neurons from patients with BD, a condition characterized in a subgroup of patients by dysregulated WNT/β-catenin signaling. Overall, the findings show that distinct ASD, SZ and BD candidate genes converge on common molecular targets - an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.

2017-02-16 | GSE85417 | GEO

A protein interaction network of mental disorder factors in neural stem cells

Project description:Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disabilities (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with these MDs have been identified by high-throughput sequencing technology. A substantial fraction of these mutations is in genes encoding proteins involved in transcriptional regulation. It is unclear whether different MD-associated transcriptional regulators act in the same gene regulatory network. Such information is important to appreciate the underlying etiology of an MD and the molecular relatedness of different MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we purified several MD-associated transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing over 200 proteins. The interaction network is enriched for protein factors associated with ID, ASD or schizophrenia and enriched for protein factors encoded by evolutionary constrained genes. Our network thereby provides molecular connections between established MD factors and a discovery tool for novel MD genes. We identified interactions between many transcriptional regulators with a different MD association. We show that network factors preferentially co-localize on the genome and cooperate in the regulation of disease-relevant genes to explain overlapping phenotypes in different syndromes. Our results suggest that the observed transcriptional regulators associated with ID, schizophrenia or ASD are part of the same transcriptional network. We find that the severity of mutations in network factors increased with the severity of the associated MD, suggesting that the level of disruption of a common transcriptional network affects mental disorder outcome.

2016-12-22 | GSE70872 | GEO

Comorbidities - microcephaly, facial dysmorphia and epilepsy - increase the risk of the pathogenic CNV finding in patients with intellectual disability and autism

Project description:CNV are known to be a frequent cause of the autism spectrum disorders (ASD) and intellectual disabilities (ID). However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. We conclude that comorbidities such as microcephaly, facial dysmorphia and epilepsy increase the risk of the pathogenic CNV finding in patients with ID and ASD. However, the significance of these comorbidities differs between both groups and shows dependency on whether the patients were primarily classified as ID or ASD. We suggest that stratification of the patients according to their comorbidities before testing can increase the yield of the detection rate of pathogenic CNV in both groups. The likelihood of pathogenic CNV detection in ASD patients without any comorbidities is low. Therefore, the effectivity of CNV analysis in these cases is modest

2019-06-11 | GSE132453 | GEO

Large rare Deletions in Ashkenazi Jewish schizophrenia cases vs controls

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

Large rare Deletions in Ashkenazi Jewish schizophrenia cases vs controls

2010-08-06 | GSE23201 | GEO