Abstract
Antisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2-sensitivite lncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase gene ctt1 revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT. Interestingly, expression of this asXUT was also activated in wild-type cells upon oxidative stress, concomitant to ctt1 induction, indicating a potential attenuation feedback. This attenuation correlates with asXUT abundance, it is transcriptional, characterized by low RNAPII-ser5 phosphorylation, and it requires an histone deacetylase activity and the conserved Set2 histone methyltransferase. Finally, we identified Dicer as another RNA processing factor acting on ctt1 induction, but independently of Exo2. We propose that asXUTs could modulate the expression of their paired-sense genes when it exceeds a critical threshold, using a conserved mechanism independent of RNAi.
Highlights
Eukaryotic genomes are pervasively transcribed [1], generating plenty of non-coding transcripts, distinct from the housekeeping rRNAs, tRNAs and sn(o)RNAs, and that are arbitrarily classified into small (< 200 nt) and long (! 200 nt) ncRNAs [2,3].Long (l)ncRNAs are produced by RNA polymerase II (RNAPII), capped and polyadenylated, yet lack protein-coding potential [4,5], this last point is subject to exceptions [6].Several lines of evidence suggest that they are functionally important
Examples of regulatory antisenselncRNAs acting on gene expression have been reported in multiple model organisms
Our previous studies in budding and fission yeasts revealed that aslncRNAs are actively degraded by the Xrn1/Exo2-dependent cytoplasmic 5’-3’ RNA decay pathway
Summary
Eukaryotic genomes are pervasively transcribed [1], generating plenty of non-coding (nc) transcripts, distinct from the housekeeping rRNAs, tRNAs and sn(o)RNAs, and that are arbitrarily classified into small (< 200 nt) and long (! 200 nt) ncRNAs [2,3].Long (l)ncRNAs are produced by RNA polymerase II (RNAPII), capped and polyadenylated, yet lack protein-coding potential [4,5], this last point is subject to exceptions [6].Several lines of evidence suggest that they are functionally important. Eukaryotic genomes are pervasively transcribed [1], generating plenty of non-coding (nc) transcripts, distinct from the housekeeping rRNAs, tRNAs and sn(o)RNAs, and that are arbitrarily classified into small (< 200 nt) and long Long (l)ncRNAs are produced by RNA polymerase II (RNAPII), capped and polyadenylated, yet lack protein-coding potential [4,5], this last point is subject to exceptions [6]. Several lines of evidence suggest that they are functionally important. LncRNAs show tissue-specific expression [7] and respond to diverse stimuli, such as oxidative stress [8], suggesting that their expression is precisely controlled. There is a growing repertoire of cellular processes in which lncRNAs play important roles, including Xchromosome inactivation, imprinting, maintenance of pluripotency and transcriptional regulation [12,13]
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