Modeling the functional genomics of autism using human neurons.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Genevieve Konopka
PROVIDER: E-GEOD-28046 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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.
2011-06-01 | GSE28046 | GEO
Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with âintrinsic autismâ, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell. We generated induced pluripotent stem cells (iPSCs) from male patients with intrinsic autism, their unaffected male siblings, and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons following 80 days of post-mitotic neural differentiation. These samples, including fibroblast, iPSC, iPSC-derived neural progenitors (NPC) and iPSC-derived neurons, were analyzed for the change of gene expression profile by whole genome microarray.
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Project description:Studies investigating the causes of autism spectrum disorder (ASD) point to genetic as well as epigenetic mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here we identify the bromodomain and extra-terminal domain containing transcriptional regulators (BETs) as epigenetic drivers of an ASD-like disorder in mice. We found that the pharmacological suppression of the BET proteins by a novel, highly selective and brain-permeable inhibitor, I-BET858, leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome in mice. Many of the I-BET858 affected genes have been linked to ASD in humans thus suggesting the key role of the BET-controlled gene network in ASD. Our studies also suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD. There are 24 total samples. There are two timepoints, 2 and 12 hours. Triplicates were performed for each treatment. Control samples were prepared by treating with DMSO for each of the timepoints.
2015-09-09 | E-GEOD-72149 | biostudies-arrayexpress
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.
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Project description:Chromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance may contribute to the significant enlargement of cerebral organoids in line with the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.
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Project description:Synaptic dysfunction represents a key pathophysiology in neurodevelopmental disorders such as autism spectrum disorder (ASD). Rare mutation R451C in human Neuroligin 3 (NLGN3, encoded by X-linked gene NLGN3), a cell adhesion molecule essential for synapse formation, has been linked to ASD. Despite success in recapitulating the social interaction behavioral deficits and the underlying synaptic abnormalities in mouse model, the impact of NLGN3 R451C on the human neuronal system remains elusive. Here, we generated isogenic knock-in human pluripotent stem cell lines harboring NLGN3 R451C allele and examined its impact on synaptic transmission. Analysis of co-cultured excitatory and inhibitory induced neurons (iNs) with mutation revealed an augmentation in excitatory synaptic strength comparing to isogenic control, but not in inhibitory synaptic transmission. Consistently, the augmentation in excitatory transmission was confirmed in iNs transplanted into mouse forebrain. Using single-cell RNA seq on co-cultured excitatory and inhibitory iNs, we identified differential expression genes (DEGs) and found NLGN3 R451C alters gene networks associated with synaptic transmission. Gene ontology and enrichment analysis revealed convergent gene networks associated with ASD and other mental disorders. Our finding suggests that the NLGN3 R451C mutation could preferentially impact excitatory neurons, which causes overall network properties changes and excitation-inhibition imbalance related to mental disorders.
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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.
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