Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
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PROVIDER: PRJNA511583 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: The transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls was examined over a 135-day course of neuronal differentiation using RNAseq analysis Methods: Induced pluripotent stem cells (5 control iPSC and 6 ASD-specific iPSC) were differentiated into cortical neurons and RNA samples were obtained at two different time points day 35 post differentiation and day 135 post differentiation. RNAseq was performed from the RNA isolated at the different time points and the differentially expressed genes identified. Pathway analysis for gene ontology and biological processes, as well as, weighted gene co-expression network analysis was performed. Results: The results of this analysis show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. Conclusions: Transcriptional analyses of the ASD and control neurons showed ASD-specific molecular phenotypes affecting networks involved in neuronal differentiation, the cytoskeletal matrix structure formation, patterning, DNA and RNA metabolism.
2018-12-24 | GSE124308 | GEO
Project description:Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.
| S-EPMC5976773 | biostudies-literature
Project description: Not available
| S-EPMC8873475 | biostudies-literature
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: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.
2011-05-01 | GSE28521 | GEO
Project description:Pintacuda G*, Hsu YH*, Tsafou K, Li KW, Martín JM, Riseman J, Biagini JC, Ching JKT, Mena D, Gonzalez-Lozano MA, Egri SB, Jaffe J, Smit AB, Fornelos N, Eggan KC, Lage K. Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. Cell Genomics (2023). [DOI: https://doi.org/10.1016/j.xgen.2022.100250] Autism spectrum disorders (ASD) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the network data to show that the ASD-linked brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and to characterize a PTEN-AKAP8L interaction that influences neuronal growth. The IGF2BP1-3 complex emerged as a convergent point in the network that may regulate a transcriptional circuit of ASD-associated genes. Our findings showcase cell-type-specific interactomes as a framework to complement genetic and transcriptomic data, and illustrate how both individual and convergent interactions can lead to biological insights into ASDs.
2023-01-17 | GSE178896 | GEO
Project description:Multiplexed single-cell autism modeling reveals convergent mechanisms altering neuronal differentiation
| PRJNA595864 | ENA
Project description:Pintacuda G*, Hsu YH*, Tsafou K, Li KW, Martín JM, Riseman J, Biagini JC, Ching JKT, Mena D, Gonzalez-Lozano MA, Egri SB, Jaffe J, Smit AB, Fornelos N, Eggan KC, Lage K. Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. Cell Genomics (2023). [DOI: https://doi.org/10.1016/j.xgen.2022.100250]
2021-06-21 | MSV000087676 | MassIVE
Project description:Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.
2022-05-09 | GSE197618 | GEO
Project description:We performed aCGH analysis using a custom Agilent oligonucleotide array to analyze 288 probands with idiopathic autism spectrum disorder (ASD) from the Simons Simplex Collection (SSC) of autism samples. The array is customized to high resolution coverage of exons for genes identified as encoding proteins included in a detailed protein interaction network for autism.
2011-06-08 | GSE29576 | GEO