Trans-genetic effects of circular RNA expression quantitative trait loci and potential causal mechanisms in autism

Mai, Te-Lun; Chen, Chia-Ying; Chiang, Tai-Wei; Chuang, Trees‐Juen

doi:10.21203/rs.3.rs-155043/v1

Cited by 3 publications

References 65 publications

(118 reference statements)

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

Watts

Oksanen

Lejerkrans

et al. 2022

Preprint

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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.

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

Watts

Oksanen

Lejerkrans

et al. 2022

Preprint

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An integrative framework for circular RNA quantitative trait locus discovery with application in human T cells

Nguyen

2023

Preprint

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Molecular quantitative trait locus (QTL) mapping of genetic variants with intermediate molecular phenotypes has proven to be a powerful approach for prioritizing genetic regulatory variants and causal genes identified by Genome-wide association studies (GWAS). Recently, this success has been extended to circular RNA (circRNA), a potential group of RNAs that can serve as markers for the diagnosis, prognosis, or therapeutic targets of cancer, cardiovascular, and autoimmune diseases. However, the detection of circRNA QTL (circQTL) is currently heavily reliant on a single circRNA detection algorithm for circRNA annotation and quantification which implies limitations in both sensitivity and specificity. In this study, we show that circQTL results produced by different circRNA calling tools are extremely divergent, making difficulties in interpretation. To resolve this issue, we develop an integrative method for circQTL mapping and implement it as an automated, reproducible, and scalable, and easy-to-use framework based on Nextflow, named cscQTL. Compared to the existing approach, the new method effectively identify circQTLs with an increase of 20-100% circQTLs detected and recovered all circQTLs that are highly supported by the single method approach. We apply the new method to a dataset of human T cells and discover genetic variants that control the expression of 55 circRNAs. By collocation analysis, we further identify circBACH2 and circYY1AP1 as potential candidates for immune disease regulation. cscQTL is freely available at: https://github.com/datngu/cscQTL.

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

et al. 2023

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Background Circular RNA (circRNA) molecules, generated through non-canonical back-splicing of exon-exon junctions, have recently been implicated in diverse biological functions including transcriptional regulation and modulation of protein interactions. 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. Results 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 associated with synaptic function. Interestingly, when assessing population data, exons giving rise to circRNAs in our dataset had a higher frequency of genetic variants. Additionally, screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which were reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. Conclusions 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.

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Trans-genetic effects of circular RNA expression quantitative trait loci and potential causal mechanisms in autism

Cited by 3 publications

References 65 publications

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

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

An integrative framework for circular RNA quantitative trait locus discovery with application in human T cells

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

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