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Human cells contain myriad excised linear introns with potential functions in gene regulation and as RNA biomarkers

By Jun Yao, Hengyi Xu, Shelby Winans, Douglas C Wu, Manuel Ares, Alan M Lambowitz

Posted 09 Sep 2020
bioRxiv DOI: 10.1101/2020.09.07.285114

We used thermostable group II intron reverse transcriptase sequencing (TGIRT-seq), which gives full-length end-to-end sequence reads of structured RNAs, to identify > 8,500 short full-length excised linear intron (FLEXI) RNAs ([≤] 300 nt) originating from > 3,500 different genes in human cells and tissues. FLEXIs are distinguished from other introns by their accumulation as stable full-length linear RNAs. Subsets of the detected FLEXI correspond to pre-miRNAs of annotated mirtrons (introns that fold into a stem-loop structure and are processed by DICER into functional miRNAs) or agotrons (structured introns that bind AGO2 and function in a miRNA-like manner) and a few encode snoRNAs, but the vast majority had not been identified previously. FLEXI RNA profiles are cell-type specific, reflecting differences in transcription, alternative splicing, and intron RNA turnover, and comparisons of matched tumor and healthy tissues from breast cancer patients and cell lines revealed hundreds of differences in FLEXI RNA expression. About half the detected FLEXI RNAs contained a CLIP-seq identified binding site for one or more RNA-binding proteins. In addition to proteins that have RNA splicing- or miRNA-related functions, proteins that bind groups of 30 or more different FLEXI RNAs include transcription factors, chromatin remodeling proteins, and proteins involved in cellular stress responses and growth regulation, raising the possibility of previously unsuspected connections between intron RNAs and cellular regulatory pathways. Our findings identify a large new class of human introns with potential to serve as RNA biomarkers.

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