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Gene Regulation Analysis Reveals Perturbations of Autism Spectrum Disorder during Neural System Development.

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that impedes patients' cognition, social, speech and communication skills. ASD is highly heterogeneous with a variety of etiologies and clinical manifestations. The prevalence rate of ASD increased steadily in recent years. Presently, molecular mechanisms underlying ASD occurrence and development remain to be elucidated. Here, we integrated multi-layer genomics data to investigate the transcriptome and pathway dysregulations in ASD development. The RNA sequencing (RNA-seq) expression profiles of induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs) and neuron cells from ASD and normal samples were compared in our study. We found that substantially more genes were differentially expressed in the NPCs than the iPSCs. Consistently, gene set variation analysis revealed that the activity of the known ASD pathways in NPCs and neural cells were significantly different from the iPSCs, suggesting that ASD occurred at the early stage of neural system development. We further constructed comprehensive brain- and neural-specific regulatory networks by incorporating transcription factor (TF) and gene interactions with long 5 non-coding RNA(lncRNA) and protein interactions. We then overlaid the transcriptomes of different cell types on the regulatory networks to infer the regulatory cascades. The variations of the regulatory cascades between ASD and normal samples uncovered a set of novel disease-associated genes and gene interactions, particularly highlighting the functional roles of ELF3 and the interaction between STAT1 and lncRNA ELF3-AS 1 in the disease development. These new findings extend our understanding of ASD and offer putative new therapeutic targets for further studies.

SUBMITTER: Li D

PROVIDER: S-EPMC8700980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Selective or 'picky' eating habits are common among those with autism spectrum disorder (ASD). These behaviors are often related to aberrant sensory experience in individuals with ASD, including heightened reactivity to food taste and texture. However, very little is known about the neural mechanisms that underlie taste reactivity in ASD. In the present study, food-related neural responses were evaluated in 21 young adult and adolescent males diagnosed with ASD without intellectual disability, and 21 typically-developing (TD) controls. Taste reactivity was assessed using the Adolescent/Adult Sensory Profile, a clinical self-report measure. Functional magnetic resonance imaging was used to evaluate hemodynamic responses to sweet (vs. neutral) tastants and food pictures. Subjects also underwent resting-state functional connectivity scans.The ASD and TD individuals did not differ in their hemodynamic response to gustatory stimuli. However, the ASD subjects, but not the controls, exhibited a positive association between self-reported taste reactivity and the response to sweet tastants within the insular cortex and multiple brain regions associated with gustatory perception and reward. There was a strong interaction between diagnostic group and taste reactivity on tastant response in brain regions associated with ASD pathophysiology, including the bilateral anterior superior temporal sulcus (STS). This interaction of diagnosis and taste reactivity was also observed in the resting state functional connectivity between the anterior STS and dorsal mid-insula (i.e., gustatory cortex).These results suggest that self-reported heightened taste reactivity in ASD is associated with heightened brain responses to food-related stimuli and atypical functional connectivity of primary gustatory cortex, which may predispose these individuals to maladaptive and unhealthy patterns of selective eating behavior.Trial registration(clinicaltrials.gov identifier) NCT01031407. Registered: December 14, 2009.

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Gene Regulation Analysis Reveals Perturbations of Autism Spectrum Disorder during Neural System Development.

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