Conserved protein Pir2ARS2 mediates gene repression through cryptic introns in lncRNAs

Abstract

Long non-coding RNAs (lncRNAs) are components of epigenetic control mechanisms that ensure appropriate and timely gene expression. The functions of lncRNAs are often mediated through associated gene regulatory activities, but how lncRNAs are distinguished from other RNAs and recruit effector complexes is unclear. Here, we utilize the fission yeast Schizosaccharomyces pombe to investigate how lncRNAs engage silencing activities to regulate gene expression in cis. We find that invasion of lncRNA transcription into the downstream gene body incorporates a cryptic intron required for repression of that gene. Our analyses show that lncRNAs containing cryptic introns are targeted by the conserved Pir2 ARS2 protein in association with splicing factors, which recruit RNA processing and chromatin-modifying activities involved in gene silencing. Pir2 and splicing machinery are broadly required for gene repression. Our finding that human ARS2 also interacts with splicing factors suggests a conserved mechanism mediates gene repression through cryptic introns within lncRNAs.

Centromeric Transcription: A Conserved Swiss-Army Knife

“…Nevertheless, polyadenylation isolation protocols consistently detect centromeric transcripts across kingdoms ( Table 1 ), providing evidence that cenRNAs can be processed like lncRNAs and mRNAs. These two latter groups of transcripts also tend to undergo splicing events to produce mature transcripts [ 91 , 92 ]. Indeed, centromeric RNAs are associated with splicing factors ( Table 1 ).…”

Long Non-Coding RNAs in the Control of Gametogenesis: Lessons from Fission Yeast

“…machinery and chromatin-modifying enzymes (Figure 3b) [78]. As such, mutations in cisacting cryptic introns or of the above-mentioned trans-acting factors result in a substantial increase in the expression of downstream genes (e.g., byr2+).…”

“…As such, mutations in cisacting cryptic introns or of the above-mentioned trans-acting factors result in a substantial increase in the expression of downstream genes (e.g., byr2+). Importantly, sporulation defects due to byr2+ repression by increased nam1 levels in cells lacking the exosome component Rrp6 [34] are rescued upon the mutation of Pir2 or splicing factors [78]. Thus, the regulation of nam1 termination provides a highly flexible, lncRNA-dependent system for cells to control commitment to meiosis.…”

“…This is facilitated by telomere clustering at Recent work further unveiled a mechanism by which lncRNAs, including nam1, mediate the repression of neighboring genes. Notably, read-through transcription allows lncRNAs to incorporate cryptic introns that are recognized by the conserved Pir2 protein and splicing factors, which in turn recruit gene silencing effectors, including the RNAi machinery and chromatin-modifying enzymes (Figure 3b) [78]. As such, mutations in cisacting cryptic introns or of the above-mentioned trans-acting factors result in a substantial increase in the expression of downstream genes (e.g., byr2+).…”

Cytoplasmic Switch of ARS2 Isoforms Promotes Nonsense-Mediated mRNA Decay and Arsenic Sensitivity

“…Previous work has shown that CBC complex component NCBP1 promotes NMD in the cytoplasm 9,18 . Additional studies have reported the interaction between ARS2 and several components of the NMD pathway 5,19,20 . However, the question of whether ARS2 participates in NMD has not been addressed.…”