Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma

Grosso, Ana Rita; Leite, Ana Paula; Carvalho, Sílvia; Matos, Maria Margarida Nunes Gaspar de; Martins, Filipa; Vítor, Alexandra C; Desterro, Joana; Carmo‐Fonseca, Maria; Almeida, Sérgio Fernandes de

doi:10.7554/elife.09214

Cited by 127 publications

(116 citation statements)

References 24 publications

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“…This allows many RNAs to be generated from intergenic regions (Vilborg et al, 2015) and, in fact, the global efficiency of termination is known to change in cancer (Grosso et al, 2015; Kannan et al, 2011; Maher et al, 2009), viral infection (Nemeroff et al, 1998; Rutkowski et al, 2015), and osmotic stress (Vilborg et al, 2015). Once produced, some readthrough transcripts have been proposed to help maintain the nuclear scaffold during osmotic stress (Vilborg et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

et al. 2017

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SUMMARY Many eukaryotic genes generate linear mRNAs and circular RNAs, but it is largely unknown how the ratio of linear to circular RNA is controlled or modulated. Using RNAi screening in Drosophila cells, we identify many core spliceosome and transcription termination factors that control the RNA outputs of reporter and endogenous genes. When spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased. Upon inhibiting RNA polymerase II termination via depletion of the cleavage/polyadenylation machinery, circular RNA levels were similarly increased. This is because readthrough transcripts now extend into downstream genes and are subjected to backsplicing. In total, these results demonstrate that inhibition or slowing of canonical pre-mRNA processing events shifts the steady-state output of protein-coding genes towards circular RNAs. This is in part because nascent RNAs become directed into alternative pathways that lead to circular RNA production.

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Section: Discussionmentioning

confidence: 99%

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

et al. 2017

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“…Upon osmotic, oxidative or heat stress, transcriptional patterns of thousands of genes show prolonged Pol II progression, extending several kilobases further downstream of the PAS than observed in non-stress conditions 119 . Reduced poly(A)-processing has been coupled to read-through transcription 120–122 , and RNA-seq studies indicate that read-through transcription, indeed, produces long RNA molecules that mostly remain in the nucleus 119 (FIG. 5).…”

Section: Co-transcriptional Processingmentioning

confidence: 99%

Molecular mechanisms driving transcriptional stress responses

Vihervaara¹,

Duarte²,

Lis³

2018

Nat Rev Genet

216

224

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Proteotoxic stress, that is, stress caused by protein misfolding and aggregation, triggers the rapid and global reprogramming of transcription at genes and enhancers. Genome-wide assays that track transcriptionally-engaged RNA polymerase II (Pol II) at nucleotide resolution have provided key insights into the underlying molecular mechanisms that regulate transcriptional responses to stress. In addition, recent kinetic analyses on transcriptional control under heat stress have shown how cells ‘prewire’ and rapidly execute genome-wide changes in transcription while concurrently becoming poised for recovery. The regulation of Pol II at genes and enhancers in response to heat stress is coupled to chromatin modification and compartmentalization, as well as to co-transcriptional RNA processing. These mechanistic features seem to apply broadly to other coordinated genome-regulatory responses.

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“…Recent studies reveal that stress can reduce the efficiency of transcription termination (8)(9)(10). Transcription termination involves elongation through the cleavage and polyadenylation (polyA) signal and subsequent cleavage of the nascent RNA, followed by the addition of nontemplated A residues to the 3′ end to produce an mRNA.…”

mentioning

confidence: 99%

“…Typically, the extended RNA is quickly degraded by exonucleases that access the unprotected 5′ end generated by cleavage at the polyA site (12,13). However, recent studies show that various stress and disease states, including osmotic stress (10), HSV-1 infection (9), and renal carcinoma (8), increase both the levels and length of transcripts mapping to regions downstream of the cleavage and polyadenylation sites. Our previous study (10) showed that these transcripts are continuous with the RNAs generated from the upstream protein-coding gene, suggesting that they result from alterations in cleavage and polyadenylation and/or termination events.…”

mentioning

confidence: 99%

Comparative analysis reveals genomic features of stress-induced transcriptional readthrough

Vilborg

Sabath

Wiesel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

148

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Transcription is a highly regulated process, and stress-induced changes in gene transcription have been shown to play a major role in stress responses and adaptation. Genome-wide studies reveal prevalent transcription beyond known protein-coding gene loci, generating a variety of RNA classes, most of unknown function. One such class, termed downstream of gene-containing transcripts (DoGs), was reported to result from transcriptional readthrough upon osmotic stress in human cells. However, how widespread the readthrough phenomenon is, and what its causes and consequences are, remain elusive. Here we present a genome-wide mapping of transcriptional readthrough, using nuclear RNA-Seq, comparing heat shock, osmotic stress, and oxidative stress in NIH 3T3 mouse fibroblast cells. We observe massive induction of transcriptional readthrough, both in levels and length, under all stress conditions, with significant, yet not complete, overlap of readthrough-induced loci between different conditions. Importantly, our analyses suggest that stress-induced transcriptional readthrough is not a random failure process, but is rather differentially induced across different conditions. We explore potential regulators and find a role for HSF1 in the induction of a subset of heat shock-induced readthrough transcripts. Analysis of public datasets detected increases in polymerase II occupancy in DoG regions after heat shock, supporting our findings. Interestingly, DoGs tend to be produced in the vicinity of neighboring genes, leading to a marked increase in their antisense-generating potential. Finally, we examine genomic features of readthrough transcription and observe a unique chromatin signature typical of DoG-producing regions, suggesting that readthrough transcription is associated with the maintenance of an open chromatin state.transcriptional readthrough | stress response | transcription regulation

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Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma

Cited by 127 publications

References 24 publications

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

Molecular mechanisms driving transcriptional stress responses

Comparative analysis reveals genomic features of stress-induced transcriptional readthrough

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