Post-transcriptional dysregulation in autism, schizophrenia, and bipolar disorder

The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of post-transcriptional mechanisms; however, the role of the latter underlying many diseases remains relatively unknown. By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ), and controls, we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders. Approximately 30% of the expression variability was attributed to post-transcriptional dysregulation. Interestingly, mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD, leading to the inhibition of neurogenesis and neural differentiation, while upregulated in ASD, resulting in enhanced activity of apoptosis. These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders. An RNA-binding protein, ELAVL3, was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders. To validate, we knocked down its expression in cerebral organoids. Not only did differentially expressed genes in ELAVL3-knockdown cover a considerable proportion of predicted targets in three disorders, but we also found neurogenesis was significantly affected, given the diminished proliferation and consequently the reduced size of the organoids. Our study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.