A foundational atlas of autism protein interactions reveals molecular convergence [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1202137 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31811205_1.fastq.gz | Fastqsanger.gz | |||
| SRR31811205_2.fastq.gz | Fastqsanger.gz | |||
| SRR31811206_1.fastq.gz | Fastqsanger.gz | |||
| SRR31811206_2.fastq.gz | Fastqsanger.gz | |||
| SRR31811207_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Systematic mapping of protein-protein interaction (PPI) networks and determining how causal mutations rewire them in autism spectrum disorder (ASD) provide a powerful framework for uncovering disease mechanisms and therapeutic opportunities. Using affinity purification-mass spectroscopy (AP-MS), we systematically mapped PPIs for 100 high-confidence ASD genes, uncovering over 1,800 interactions. By assessing the impact of pathogenic missense mutations, leveraging AlphaFold, and validating key findings in human-derived model systems, we identify marked convergence onto shared protein complexes in the wild-type state and convergent PPI rewiring driven by independent mutations. For example, distinct patient-derived variants in FOXP1 disrupt its interactions with FOXP4, leading to changes in cortical neurogenesis and neural activity in brain organoids. Overall, these findings link genetic variation to protein networks and convergent neurodevelopmental dysfunction in ASD.
2024-12-25 | GSE285270 | GEO
Project description:Neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ), involve widespread transcriptional dysregulation. Copy number variations (CNVs) at 16p11.2 are among the strongest genetic risk factors for ASD and SCZ, yet the molecular mechanisms by which these CNV contribute to neurodevelopmental pathology remain unclear. Here, we identify significant genetic associations between ASD susceptibility and the HIST1 histone gene cluster through genome-wide analysis. Transcriptomic profiling across multiple experimental systems—including postmortem human brain tissue, patient-derived neural progenitor cells (NPCs), neurons, and cerebral organoids—reveals consistently elevated expression of histone variants H1.2 and H1.5 in idiopathic ASD and in 16p11.2 CNV carriers with ASD or SCZ, but not in idiopathic SCZ or bipolar disorder. Functional assays demonstrate that dysregulated H1 expression disrupts networks involved in synaptic signalling, chromatin remodelling, and neural differentiation. Using a deep learning framework incorporating Variational Autoencoder (VAE) and SHAP-based feature importance, we uncover distinct regulatory pathways driven by H1 overexpression. Notably, this overexpression induces bidirectional transcriptional changes within the 16p11.2 locus, mirroring expression signatures of both deletions and duplications. Our findings establish H1.2 and H1.5 as key regulators of transcriptional programs in neurodevelopmental disorders, highlighting chromatin-mediated mechanisms underlying ASD and SCZ and their potential as biomarkers.
2025-05-25 | GSE292323 | GEO
Project description:Ultimately, autism is classified as an early neurodevelopmental disorder, highly heterogeneous and with a heritability of between 40% and 90%. Transcriptome studies have already been done in subjects with autism, but we decided to perform such a study on our own cohort of Sicilian subjects with autism. the results obtained show the involvement of differentially expressed genes involving inflammatory mechanisms and the mitochondrilae system.
2024-09-09 | E-MTAB-13871 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) is a common, highly heritable neuro-developmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an etiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1/FOX1, and a module enriched for immune genes and glial markers. Using high-throughput RNA-sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in ASD brain. Moreover, using a published autism GWAS dataset, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. Total RNA was extracted from approximately 100mg of postmortem brain tissue representing Cerebellum (C), Frontal cortex (F), and Temporal cortex (T), from autistic and control individuals.
2011-05-01 | E-GEOD-28521 | biostudies-arrayexpress
Project description:The PHIP chromatin reader protein is mutated in Chung-Jansen syndrome, a neurodevelopmental disorder with autism like symptoms. Here we have characterized the chromatin binding properties of PHIP using a variety of in vitro and in vivo methods.
2021-11-22 | GSE189235 | GEO
Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. [Mouse] 5 biological replicates of transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated controls; Pol2 ChIPseq of topotecan and vehicle treated neurons [Human] Transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated control.
2013-08-30 | E-GEOD-43526 | biostudies-arrayexpress
Project description:We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism. Primary normal human neuronal progenitors differentiation for 0, 2, 4, or 8 weeks.
2011-06-01 | E-GEOD-28046 | biostudies-arrayexpress
Project description:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE263334 | GEO
Project description:As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes.
2017-06-23 | GSE100387 | GEO
Project description:Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.
2025-04-05 | GSE288732 | GEO