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Genome Biol. 2012 May 24;13(5):R35. doi: 10.1186/gb-2012-13-5-r35.

Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns.

Author information

1
The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK2200 Copenhagen, Denmark. bo.porse@finsenlab.dk

Abstract

BACKGROUND:

Nonsense-mediated mRNA decay (NMD) affects the outcome of alternative splicing by degrading mRNA isoforms with premature termination codons. Splicing regulators constitute important NMD targets; however, the extent to which loss of NMD causes extensive deregulation of alternative splicing has not previously been assayed in a global, unbiased manner. Here, we combine mouse genetics and RNA-seq to provide the first in vivo analysis of the global impact of NMD on splicing patterns in two primary mouse tissues ablated for the NMD factor UPF2.

RESULTS:

We developed a bioinformatic pipeline that maps RNA-seq data to a combinatorial exon database, predicts NMD-susceptibility for mRNA isoforms and calculates the distribution of major splice isoform classes. We present a catalog of NMD-regulated alternative splicing events, showing that isoforms of 30% of all expressed genes are upregulated in NMD-deficient cells and that NMD targets all major splicing classes. Importantly, NMD-dependent effects are not restricted to premature termination codon+ isoforms but also involve an abundance of splicing events that do not generate premature termination codons. Supporting their functional importance, the latter events are associated with high intronic conservation.

CONCLUSIONS:

Our data demonstrate that NMD regulates alternative splicing outcomes through an intricate web of splicing regulators and that its loss leads to the deregulation of a panoply of splicing events, providing novel insights into its role in core- and tissue-specific regulation of gene expression. Thus, our study extends the importance of NMD from an mRNA quality pathway to a regulator of several layers of gene expression.

PMID:
22624609
PMCID:
PMC3446288
DOI:
10.1186/gb-2012-13-5-r35
[Indexed for MEDLINE]
Free PMC Article

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