Circular RNAs arising from synaptic host genes are modulated by SFPQ RNA-binding protein and increased during human neuronal differentiation

Circular RNAs (circRNAs) are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored. Using total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes with synaptic functions. Interestingly, when assessing population data and rare de novo variants in autism spectrum disorder (ASD) candidate host genes, exons giving rise to circRNAs had a significantly higher frequency of genetic variants. Screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which we validated as being reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. Our study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation.