Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation

The rate of RNA polymerase II (Pol II) elongation can influence splice site selection in nascent transcripts, yet the extent and physiological relevance of this kinetic coupling between transcription and alternative splicing (AS) is not well understood. We performed experiments to perturb Pol II elo...

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Bibliographic Details
Published in:Genome research 2011-03, Vol.21 (3), p.390-401
Main Authors: Ip, Joanna Y, Schmidt, Dominic, Pan, Qun, Ramani, Arun K, Fraser, Andrew G, Odom, Duncan T, Blencowe, Benjamin J
Format: Article
Language:English
Subjects:
Alternative Splicing
Codon, Nonsense - genetics
Codon, Nonsense - metabolism
Enzyme Inhibitors - pharmacology
Exons
Gene Expression Regulation
Genome, Human
Humans
Jurkat Cells
Microarray Analysis
Molecular Targeted Therapy
RNA Polymerase II - antagonists & inhibitors
RNA Polymerase II - genetics
RNA Polymerase II - metabolism
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-Binding Proteins - metabolism
Transcription, Genetic
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Summary:The rate of RNA polymerase II (Pol II) elongation can influence splice site selection in nascent transcripts, yet the extent and physiological relevance of this kinetic coupling between transcription and alternative splicing (AS) is not well understood. We performed experiments to perturb Pol II elongation and then globally compared AS patterns with genome-wide Pol II occupancy. RNA binding and RNA processing functions were significantly enriched among the genes with Pol II elongation inhibition-dependent changes in AS. Under conditions that interfere with Pol II elongation, including cell stress, increased Pol II occupancy was detected in the intronic regions flanking the alternative exons in these genes, and these exons generally became more included. A disproportionately high fraction of these exons introduced premature termination codons that elicited nonsense-mediated mRNA decay (NMD), thereby further reducing transcript levels. Our results provide evidence that kinetic coupling between transcription, AS, and NMD affords a rapid mechanism by which cells can respond to changes in growth conditions, including cell stress, to coordinate the levels of RNA processing factors with mRNA levels.
ISSN:1088-9051
1549-5469
DOI:10.1101/gr.111070.110