Cryptic unstable transcripts (CUTs) are synthesized from intra-and intergenic regions in Saccharomyces cerevisiae and are rapidly degraded by RNA surveillance pathways, but their function(s) remain(s) elusive. Here, we show that an antisense TY1 CUT, starting within the Ty1 retrotransposon and encompassing the promoter 5 long terminal repeat (LTR), mediates RNA-dependent gene silencing and represses Ty1 mobility. We show that the Ty1 regulatory RNA is synthesized by RNA polymerase II, polyadenylated, and destabilized by the cytoplasmic 5 RNA degradation pathway. Moreover, the Ty1 regulatory RNA represses Ty1 transcription and transposition in trans by acting on the de novo transcribed TY1 RNA. Consistent with a transcriptional regulation mechanism, we show that RNA polymerase II occupancy is reduced on the Ty1 chromatin upon silencing, although TBP binding remains unchanged. Furthermore, the Ty1 silencing is partially mediated by histone deacetylation and requires Set1-dependent histone methylation, pointing out an analogy with heterochromatin gene silencing. Our results show the first example of an RNA-dependent gene trans-silencing mediated by epigenetic marks in S. cerevisiae. Recent data have shown that cryptic unstable transcripts (CUTs) are RNA polymerase II (RNAPII)-dependent noncoding RNAs (ncRNAs) corresponding to inter-and intragenic regions of the genome and may represent 10% of intergenic transcripts in Saccharomyces cerevisiae (Wyers et al. 2005). Under normal conditions, CUTs are almost undetectable, as they are rapidly degraded by the activity of Rrp6 and Trf4, members of the nuclear exosome and the TRAMP complex, respectively (LaCava et al. 2005;Vanacova et al. 2005;Wyers et al. 2005). In addition to Trf4 and Rrp6, the cytoplasmic 5Ј-3Ј exoribonuclease Xrn1 also plays an important role in the turnover of CUTs, supporting the idea that some of these transcripts escape the nuclear quality control and might have a cytoplasmic residency (Thompson and Parker 2007).Despite these observations, the function(s) of CUTs remain(s) poorly characterized. Cryptic transcription has been widely described from yeast to human and qualified as "transcriptional noise." Interestingly, it has been proposed that cryptic transcription allows RNA polymerase-dependent chromatin changes but not the production of functional RNA molecules, as those are immediately degraded (Struhl 2007). In agreement with this model, CUT transcription has been shown to interfere with promoters of coding regions and hence regulates gene expression in S. cerevisiae (Martens et al. 2005;Hongay et al. 2006;Uhler et al. 2007). However, alternative models emerged, providing a direct function for cryptic transcripts. Indeed, recent reports have shown that the processing of siRNAs in Schizosaccharomyces pombe is mediated by homologs of the TRAMP and exosome subunits (Buhler et al. 2007;Nicolas et al. 2007), strongly indicating that the fission yeast's siRNAs might originate from CUTs. It is tempting to hypothesize that CUTs in S. cerevisiae are link...

EMBO reports VOL 10 | NO 9 | 2009 973 review review During the past few years, it has become increasingly evident that the expression of eukaryotic genomes is far more complex than had been previously noted. The idea that the transcriptome is derived exclusively from protein-coding genes and some specific non-coding RNAs-such as snRNAs, snoRNAs, tRNAs or rRNAs-has been swept away by numerous studies indicating that RNA polymerase II can be found at almost any genomic location. Pervasive transcription is widespread and, far from being a futile process, has a crucial role in controlling gene expression and genomic plasticity. Here, we review recent findings that point to cryptic transcription as a fundamental component of the regulation of eukaryotic genomes.