RNA Exosome Depletion Reveals Transcription Upstream of Active Human Promoters

Preker, Pascal J.; Nielsen, Jørgen Feldbæk; Kammler, Susanne; Lykke‐Andersen, Søren; Christensen, Marianne S.; Mapendano, Christophe K.; Schierup, Mikkel H.; Jensen, Torben Heick

doi:10.1126/science.1164096

Cited by 695 publications

(678 citation statements)

References 15 publications

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“…Unstable, likely noncoding, transcripts can also be derived from divergent (bidirectional) transcription in both yeast and mammals (Core et al 2008;Preker et al 2008;Seila et al 2008). These may be either by-products of chromatin remodeling and recruitment of the transcription machinery to the neighboring gene's promoter or functional transcripts (Kanhere et al 2010).…”

Section: Divergently Transcribed Lincrnasmentioning

confidence: 99%

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Cabili¹,

Trapnell²,

Goff³

et al. 2011

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Large intergenic noncoding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes. Determining the function of individual lincRNAs remains a challenge. Recent advances in RNA sequencing (RNA-seq) and computational methods allow for an unprecedented analysis of such transcripts. Here, we present an integrative approach to define a reference catalog of >8000 human lincRNAs. Our catalog unifies previously existing annotation sources with transcripts we assembled from RNA-seq data collected from~4 billion RNA-seq reads across 24 tissues and cell types. We characterize each lincRNA by a panorama of >30 properties, including sequence, structural, transcriptional, and orthology features. We found that lincRNA expression is strikingly tissue-specific compared with coding genes, and that lincRNAs are typically coexpressed with their neighboring genes, albeit to an extent similar to that of pairs of neighboring protein-coding genes. We distinguish an additional subset of transcripts that have high evolutionary conservation but may include short ORFs and may serve as either lincRNAs or small peptides. Our integrated, comprehensive, yet conservative reference catalog of human lincRNAs reveals the global properties of lincRNAs and will facilitate experimental studies and further functional classification of these genes.

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Section: Divergently Transcribed Lincrnasmentioning

confidence: 99%

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Cabili¹,

Trapnell²,

Goff³

et al. 2011

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“…5 To define the extent of low abundance transcripts in human cells, Preker et al depleted an exosome subunit hRrp40 using RNA interference (RNAi). Oligo-dT primed cDNA from cells treated with either a control siRNA or siRNA to hRrp40 was subjected to analysis using ENCODE tiling arrays covering 1% of the human genome.…”

Section: Divergent Transcription In Mammalsmentioning

confidence: 99%

“…Results from a number of laboratories using different experimental techniques have found evidence for transcription occurring divergently from many promoters in yeast, 1,2 and mammals. [3][4][5] Two recent studies in mammals have shown that polymerase occupancy is nearly equivalent in both directions; however, one study demonstrates that the polymerase that is upstream and antisense to the direction of genes does not productively elongate. The other studies in yeast and mammals provide evidence that these transcribing complexes are acted on by a pathway that selectively terminates short transcripts and targets these upstream RNAs for degradation.…”

mentioning

confidence: 99%

Divergent transcription: A new feature of active promoters

Seila¹,

Core²,

Lis³

et al. 2009

Cell Cycle

168

164

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“…It is involved in the surveillance of mRNA biogenesis, the cytoplasmic turnover of mRNA, and the degradation of unstable transcripts derived from intergenic regions in the genome of the S. cerevisiae (Wyers et al, 2005;Preker et al, 2008). The exosome also plays an essential role in the processing of noncoding RNA precursors, including pre-rRNA, pre-snRNA, pre-snoRNA, and pre-tRNA (reviewed by Butler, 2002).…”

Section: Introductionmentioning

confidence: 99%

The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Hessle¹,

Björk²,

Sokolowski³

et al. 2009

MBoC

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Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins. INTRODUCTIONExpression of protein-coding genes is a complex multistep process. Precursor messenger RNAs (pre-mRNAs) are synthesized by RNA polymerase II (Pol-II) and assembled into ribonucleoprotein (RNP) complexes during transcription. The pre-mRNPs must be processed to become mature mRNPs, which are exported to the cytoplasm and translated into protein. Mutations in the DNA or errors in the transcription and processing reactions can lead to the synthesis of aberrant mRNPs. Eukaryotic cells have evolved quality control mechanisms that identify aberrant mRNPs and prevent their expression into protein. In the yeast Saccharomyces cerevisiae there are at least three nuclear steps of mRNP biogenesis that are under surveillance: the cleavage and polyadenylation of the 3Ј end (Hilleren et al., 2001), the assembly of the mRNA-protein complexes (Zenklusen et al., 2002;Luna et al., 2005), and the removal of introns (Galy et al., 2004). In all cases, mRNPs with assembly and/or processing defects are detected by nuclear surveillance mechanisms, retained in the nucleus, and degraded (reviewed by Vinciguerra and Stutz, 2004;Sommer and Nehrbass, 2005;Saguez et al., 2005). Genetic studies in S. cerevisiae have identified the nuclear exosome as a key player in the recognition and retention of defective transcripts (reviewed by Jensen et al., 2003;Houseley et al., 2006;Vanacova and Stefl, 2007;Schmid and Jensen, 2008).The exosome is a protein complex with ribonuclease activity (Mitchell et al., 1997;Allmang et al., 1999;Mitchell and Tollervey, 2000). The core of the exosome has a barrel-like architecture (reviewed by Lorentzen et al., 2008). The barrel is made of nine protein subunits organized into two rings, a hexameric ring and a trimeric ring, and the structure of the barrel is conserved throughout evolution (Lorentzen et al., 2005;Liu et al., 2006;Wang et al., 2007). Two additional proteins, Dis3/Rrp44 and R...

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RNA Exosome Depletion Reveals Transcription Upstream of Active Human Promoters

Cited by 695 publications

References 15 publications

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Divergent transcription: A new feature of active promoters

The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

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