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Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

ABSTRACT: Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question. Using RNAseq, we examined the transcriptome of iPSC-derived Neuronal Progenitor Cells (NPC) and neurons from a normocephalic ASD cohort composed mostly of high functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in NPC, and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons, while downregulated in brain samples. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142670 | GEO | 2020/02/18

REPOSITORIES: GEO

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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.

Project description:Purpose: MBD5-Associated Neurodevelopmental Disorder (MAND) is an Autism Spectrum Disorder (ASD) disorder characterized by intellectual disability, motor delay, severe speech impairment and autism-like behavioral problems. The role of MBD5 in neurodevelopmental function remains largely undefined. In this study, we explored the neurodevelopmental phenotype of 2q23.1 deletion syndrome through creating neuronal progenitor stem cells (NPC) derived from 2q23.1 patients and conducting RNA-seq to identify the contributory altered gene and to expand our knowledge about gene network differences and possible interactions between the related disease pathways and ASD. Methods: Primary skin fibroblasts from three MAND patients and four control cases were converted into induced pluripotent stem cell (iPSC) lines by transient transfections of episomal plasmids. Directed differentiation of these iPSC to NPC was accomplished with monolayer culture protocol for two weeks. Results: The RNA-seq analysis identified 498 genome-wide significant (q < 0.05) differentially expressed gene in the patients derived NPC lines as a consequence of reduced MBD5 dosage. 25 ASD associated genes were included in the differentially expressed gene list. On the top of the list, FOXG1 expression is significantly (P < 0.0001) increased in the patient derived NPC samples. The differentially expressed gene list was highly overlapped with the SFARI autism gene set, identifying biological processes that are implicating neurological phenotype and ASD such as central nervous system development, neuron differentiation, and regulation of neurogenesis. The findings of the transcriptome deviation in early neuronal stage of MAND can provide potential connection to the overlapping neurocognitive and neuropsychiatric phenotypes associated with growing risk factors, such as other chromatin modifiers and epigenetic factors that link to ASD. Such in vitro models can nurture hypotheses toward therapeutic interventions.

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Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

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