Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins

Highlights

• Unusual processing generates 5′ SnoRNA capped and 3′ PolyAdenylated (SPA) lncRNAs

• SPA processing requires a fast Pol II and snoRNP protection from XRN2 trimming

• Two SPAs that sequester multiple RBPs in hESCs are absent in PWS patients

• Knockout SPAs in hESCs leads to altered patterns of RBPs binding and splicing

Summary

We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5′ small nucleolar RNA (snoRNA) capped and 3′ polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5′ end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis.