In recent years the complexity of the eukaryotic transcriptome has become a subject of intense curiosity as well as debate. It is now well established, however, in eukaryotic organisms from yeast to humans, that RNA polymerase II (pol II) transcribes hundreds to thousands of long noncoding RNAs (lncRNAs). While our knowledge of the mechanisms and scope of lncRNA-mediated regulation is growing, our understanding of how lncRNAs themselves are regulated is still quite limited. Here I demonstrate that the abundance of many lncRNAs is regulated by decapping-dependent decay.
As pol II transcripts, messenger RNAs (mRNAs) and lncRNAs bear distinctive features at their extremities (i.e. a 5’ cap and 3’ poly(A)tail). A highly conserved pathway for the destruction of mRNAs requires removal of the cap structure (i.e. decapping) which then leaves the body of the transcript susceptible to 5’ to 3’ exonucleolytic digestion. Decapping represents a critical control point in regulating mRNA expression because it commits the transcript body to destruction. While the role of decapping in controlling mRNA levels is well documented, the contribution of decapping in modulating the levels and function of other capped RNAs has been largely unexplored.
In my study I document that decapping influences the expression of >100 lncRNAs in S. cerevisiae through a novel decapping-dependent pathway that occurs independently of all known mRNA decapping regulators. I find that decapping-sensitive lncRNAs are often expressed proximal to inducible genes. Using galactose inducible genes as a model for lncRNA-mediated regulation, I show that, upon stimulation, clearance of the lncRNA in the nucleus by decapping-dependent decay is required for rapid and robust gene activation. Failure to destabilize this lncRNA, which is known to exert repressive histone modifications, results in perpetuation of a repressive chromatin state that contributes to reduced plasticity of gene activation. I propose that decappingdependent
decay serves a vital role in regulating lncRNA-mediated epigenetic events at inducible genes.