Dataset Information

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

ABSTRACT: Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.

SUBMITTER: Parikshak NN

PROVIDER: S-EPMC7102905 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

Parikshak Neelroop N NN Swarup Vivek V Belgard T Grant TG Irimia Manuel M Ramaswami Gokul G Gandal Michael J MJ Hartl Christopher C Leppa Virpi V Ubieta Luis de la Torre LT Huang Jerry J Lowe Jennifer K JK Blencowe Benjamin J BJ Horvath Steve S Geschwind Daniel H DH

Nature 20161205 7633

Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis re ...[more]

PMID: 27919067

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Project description:Cortical circuit activity is shaped by the parvalbumin (PV) and somatostatin (SST) interneurons that inhibit principal excitatory (EXC) neurons and the vasoactive intestinal peptide (VIP) interneurons that suppress activation of other interneurons. To understand the molecular-genetic basis of functional specialization and identify potential drug targets specific to each neuron subtype, we performed a genome wide assessment of both gene expression and splicing across EXC, PV, SST and VIP neurons from male and female mouse brains. These results reveal numerous examples where neuron subtype-specific gene expression, as well as splice-isoform usage, can explain functional differences between neuron subtypes, including in presynaptic plasticity, postsynaptic receptor function, and synaptic connectivity specification. We provide a searchable web resource for exploring differential mRNA expression and splice form usage between excitatory, PV, SST, and VIP neurons (http://research-pub.gene.com/NeuronSubtypeTranscriptomes). This resource, combining a unique new dataset and novel application of analysis methods to multiple relevant datasets, identifies numerous potential drug targets for manipulating circuit function, reveals neuron subtype-specific roles for disease-linked genes, and is useful for understanding gene expression changes observed in human patient brains.SIGNIFICANCE STATEMENT Understanding the basis of functional specialization of neuron subtypes and identifying drug targets for manipulating circuit function requires comprehensive information on cell-type-specific transcriptional profiles. We sorted excitatory neurons and key inhibitory neuron subtypes from mouse brains and assessed differential mRNA expression. We used a genome-wide analysis which not only examined differential gene expression levels but could also detect differences in splice isoform usage. This analysis reveals numerous examples of neuron subtype-specific isoform usage with functional importance, identifies potential drug targets, and provides insight into the neuron subtypes involved in psychiatric disease. We also apply our analysis to two other relevant datasets for comparison, and provide a searchable website for convenient access to the resource.

Dataset Information

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

Publications

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

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