The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs

Carthew, R. W. & Sontheimer, E. J. Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642–655 (2009).

Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

Berretta, J. & Morillon, A. Pervasive transcription constitutes a new level of eukaryotic genome regulation. EMBO Rep. 10, 973–982 (2009).

Mercer, T. R., Dinger, M. E. & Mattick, J. S. Long non-coding RNAs: insights into functions. Nature Rev. Genet. 10, 155–159 (2009).

Ponting, C. P., Oliver, P. L. & Reik, W. Evolution and functions of long noncoding RNAs. Cell 136, 629–641 (2009).

Yazgan, O. & Krebs, J. E. Noncoding but nonexpendable: transcriptional regulation by large noncoding RNA in eukaryotes. Biochem. Cell Biol. 85, 484–496 (2007).

Velculescu, V. E. et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997).

Goffeau, A. 1996: a vintage year for yeast and Yeast. Yeast 12, 1603–1605 (1996).

Okazaki, Y. et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420, 563–573 (2002).

Numata, K. et al. Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection. Genome Res. 13, 1301–1306 (2003).

Hayashizaki, Y. & Carninci, P. Genome Network and FANTOM3: assessing the complexity of the transcriptome. PLoS Genet. 2, e63 (2006).

Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002).

Ravasi, T. et al. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 16, 11–19 (2006).

Kampa, D. et al. Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22. Genome Res. 14, 331–342 (2004).

Cloonan, N. & Grimmond, S. M. Transcriptome content and dynamics at single-nucleotide resolution. Genome Biol. 9, 234 (2008).

Kapranov, P., Sementchenko, V. I. & Gingeras, T. R. Beyond expression profiling: next generation uses of high density oligonucleotide arrays. Brief Funct. Genomic Proteomic 2, 47–56 (2003).

Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nature Rev. Genet. 10, 57–63 (2009).

He, Y., Vogelstein, B., Velculescu, V. E., Papadopoulos, N. & Kinzler, K. W. The antisense transcriptomes of human cells. Science 322, 1855–1857 (2008).

Carninci, P. Molecular biology: the long and short of RNAs. Nature 457, 974–975 (2009).

Carninci, P., Yasuda, J. & Hayashizaki, Y. Multifaceted mammalian transcriptome. Curr. Opin. Cell Biol. 20, 274–280 (2008).

Johnson, J. M., Edwards, S., Shoemaker, D. & Schadt, E. E. Dark matter in the genome: evidence of widespread transcription detected by microarray tiling experiments. Trends Genet. 21, 93–102 (2005).

Kapranov, P., Willingham, A. T. & Gingeras, T. R. Genome-wide transcription and the implications for genomic organization. Nature Rev. Genet. 8, 413–423 (2007).

Ponjavic, J. & Ponting, C. P. The long and the short of RNA maps. Bioessays 29, 1077–1080 (2007).

Kapranov, P. et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316, 1484–1488 (2007). The first description of promoter-associated ncRNAs in mammals.

Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008). A description of divergent small pervasive transcripts at gene promoters.

Taft, R. J. et al. Tiny RNAs associated with transcription start sites in animals. Nature Genet. 41, 572–578 (2009).

Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008). This study produced a genome-wide map of run-on transcripts in mammals that reveals bidirectional transcription at gene promoters.

Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007).

Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007).

Gilmour, D. S. Promoter proximal pausing on genes in metazoans. Chromosoma 118, 1–10 (2009).

Margaritis, T. & Holstege, F. C. Poised RNA polymerase II gives pause for thought. Cell 133, 581–584 (2008).

Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

Kim, T. H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

Fejes-Toth, K. et al. Post-transcriptional processing generates a diversity of 5′-modified long and short RNAs. Nature 457, 1028–1032 (2009).

Rasmussen, E. B. & Lis, J. T. In vivo transcriptional pausing and cap formation on three Drosophila heat shock genes. Proc. Natl Acad. Sci. USA 90, 7923–7927 (1993).

Houseley, J. & Tollervey, D. The many pathways of RNA degradation. Cell 136, 763–776 (2009).

Vanacova, S. et al. A new yeast poly(A) polymerase complex involved in RNA quality control. PLoS Biol. 3, e189 (2005).

LaCava, J. et al. RNA degradation by the exosome is promoted by a nuclear polyadenylation complex. Cell 121, 713–724 (2005).

Wyers, F. et al. Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase. Cell 121, 725–737 (2005). This study provided the first description of CUTs in yeast. In addition, in parallel with other reports, this article describes the novel poly(A) polymerase-containing complex TRAMP and its role in exosome-mediated nuclear RNA degradation.

Davis, C. A. & Ares, M. Jr. Accumulation of unstable promoter-associated transcripts upon loss of the nuclear exosome subunit Rrp6p in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 103, 3262–3267 (2006).

Neil, H. et al. Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature 457, 1038–1042 (2009).

Xu, Z. et al. Bidirectional promoters generate pervasive transcription in yeast. Nature 457, 1033–1037 (2009). References 42 and 43 report the genome-wide description of CUTs in yeast. In addition, the second article describes a novel type of more stable pervasive transcripts called SUTs. One main conclusion of both reports is that widespread bidirectional promoters generate most pervasive transcripts in yeast.

Lee, W. et al. A high-resolution atlas of nucleosome occupancy in yeast. Nature Genet. 39, 1235–1244 (2007).

O'Sullivan, J. M. et al. Gene loops juxtapose promoters and terminators in yeast. Nature Genet. 36, 1014–1018 (2004).

Preker, P. et al. RNA exosome depletion reveals transcription upstream of active human promoters. Science 322, 1851–1854 (2008).

van Hoof, A., Lennertz, P. & Parker, R. Yeast exosome mutants accumulate 3′-extended polyadenylated forms of U4 small nuclear RNA and small nucleolar RNAs. Mol. Cell Biol. 20, 441–452 (2000).

Allmang, C. et al. Functions of the exosome in rRNA, snoRNA and snRNA synthesis. EMBO J. 18, 5399–5410 (1999).

Steinmetz, E. J., Conrad, N. K., Brow, D. A. & Corden, J. L. RNA-binding protein Nrd1 directs poly(A)-independent 3′-end formation of RNA polymerase II transcripts. Nature 413, 327–331 (2001).

Carroll, K. L., Pradhan, D. A., Granek, J. A., Clarke, N. D. & Corden, J. L. Identification of cis elements directing termination of yeast nonpolyadenylated snoRNA transcripts. Mol. Cell Biol. 24, 6241–6252 (2004).

Vasiljeva, L. & Buratowski, S. Nrd1 interacts with the nuclear exosome for 3′ processing of RNA polymerase II transcripts. Mol. Cell 21, 239–248 (2006).

Ballarino, M., Morlando, M., Pagano, F., Fatica, A. & Bozzoni, I. The cotranscriptional assembly of snoRNPs controls the biosynthesis of H/ACA snoRNAs in Saccharomyces cerevisiae. Mol. Cell Biol. 25, 5396–5403 (2005).

Yang, P. K. et al. Cotranscriptional recruitment of the pseudouridylsynthetase Cbf5p and of the RNA binding protein Naf1p during H/ACA snoRNP assembly. Mol. Cell Biol. 25, 3295–3304 (2005).

Arigo, J. T., Eyler, D. E., Carroll, K. L. & Corden, J. L. Termination of cryptic unstable transcripts is directed by yeast RNA-binding proteins Nrd1 and Nab3. Mol. Cell 23, 841–851 (2006).

Thiebaut, M., Kisseleva-Romanova, E., Rougemaille, M., Boulay, J. & Libri, D. Transcription termination and nuclear degradation of cryptic unstable transcripts: a role for the Nrd1–Nab3 pathway in genome surveillance. Mol. Cell 23, 853–864 (2006). References 54 and 55 show that in yeast, the transcription of CUTs terminates by the same mechanism as the transcription of snoRNAs and that this mode of transcription termination is responsible for their rapid degradation by the nuclear exosome.

Gudipati, R. K., Villa, T., Boulay, J. & Libri, D. Phosphorylation of the RNA polymerase II C-terminal domain dictates transcription termination choice. Nature Struct. Mol. Biol. 15, 786–794 (2008).

Thompson, D. M. & Parker, R. Cytoplasmic decay of intergenic transcripts in Saccharomyces cerevisiae. Mol. Cell Biol. 27, 92–101 (2007).

Lee, A., Hansen, K. D., Bullard, J., Dudoit, S. & Sherlock, G. Novel low abundance and transient RNAs in yeast revealed by tiling microarrays and ultra high-throughput sequencing are not conserved across closely related yeast species. PLoS Genet. 4, e1000299 (2008).

Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA (2009). This paper extends the known repertoire of lincRNAs to ∼3,300 by analysing chromatin state maps in human cells. It shows that these RNAs, which are conserved across mammals, are associated with chromatin-modifying complexes, supporting the idea that they are involved in epigenetic regulatory mechanisms.

Preker, P., Nielsen, J., Schierup, M. H. & Jensen, T. H. RNA polymerase plays both sides: vivid and bidirectional transcription around and upstream of active promoters. Cell Cycle 8, 1106–1107 (2009).

Wang, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).

Morris, K. V., Santoso, S., Turner, A. M., Pastori, C. & Hawkins, P. G. Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet. 4, e1000258 (2008).

Han, J., Kim, D. & Morris, K. V. Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc. Natl Acad. Sci. USA 104, 12422–12427 (2007).

Martianov, I., Ramadass, A., Serra Barros, A., Chow, N. & Akoulitchev, A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007).

Martens, J. A., Wu, P. Y. & Winston, F. Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev. 19, 2695–2704 (2005). A landmark article that, with reference 66, analyses the first example of gene regulation by transcription interference in budding yeast.

Martens, J. A., Laprade, L. & Winston, F. Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature 429, 571–574 (2004).

Jenks, M. H., O'Rourke, T. W. & Reines, D. Properties of an intergenic terminator and start site switch that regulate IMD2 transcription in yeast. Mol. Cell Biol. 28, 3883–3893 (2008).

Kopcewicz, K. A., O'Rourke, T. W. & Reines, D. Metabolic regulation of IMD2 transcription and an unusual DNA element that generates short transcripts. Mol. Cell Biol. 27, 2821–2829 (2007).

Kuehner, J. N. & Brow, D. A. Regulation of a eukaryotic gene by GTP-dependent start site selection and transcription attenuation. Mol. Cell 31, 201–211 (2008).

Steinmetz, E. J. et al. Genome-wide distribution of yeast RNA polymerase II and its control by Sen1 helicase. Mol. Cell 24, 735–746 (2006).

Thiebaut, M. et al. Futile cycle of transcription initiation and termination modulates the response to nucleotide shortage in S. cerevisiae. Mol. Cell 31, 671–682 (2008).

Kwapisz, M. et al. Mutations of RNA polymerase II activate key genes of the nucleoside triphosphate biosynthetic pathways. EMBO J. 27, 2411–2421 (2008).

Arigo, J. T., Carroll, K. L., Ames, J. M. & Corden, J. L. Regulation of yeast NRD1 expression by premature transcription termination. Mol. Cell 21, 641–651 (2006).

Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005).

Shiraki, T. et al. Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage. Proc. Natl Acad. Sci. USA 100, 15776–15781 (2003).

Wei, C. L. et al. 5′ Long serial analysis of gene expression (LongSAGE) and 3′ LongSAGE for transcriptome characterization and genome annotation. Proc. Natl Acad. Sci. USA 101, 11701–11706 (2004).

Perocchi, F., Xu, Z., Clauder-Munster, S. & Steinmetz, L. M. Antisense artifacts in transcriptome microarray experiments are resolved by actinomycin D. Nucleic Acids Res. 35, e128 (2007).

Gingeras, T. R. Origin of phenotypes: genes and transcripts. Genome Res. 17, 682–690 (2007).

Vasiljeva, L., Kim, M., Mutschler, H., Buratowski, S. & Meinhart, A. The Nrd1–Nab3–Sen1 termination complex interacts with the Ser5-phosphorylated RNA polymerase II C-terminal domain. Nature Struct. Mol. Biol. 15, 795–804 (2008).

Carroll, K. L., Ghirlando, R., Ames, J. M. & Corden, J. L. Interaction of yeast RNA-binding proteins Nrd1 and Nab3 with RNA polymerase II terminator elements. RNA 13, 361–373 (2007).