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

Publikation: Forskning - peer reviewTidsskriftartikel

Joachim Lütken Weischenfeldt, Johannes Eichler Waage, Geng Tian, Jing Zhao, Inge Damgaard, Janus Schou Jakobsen, Karsten Kristiansen, Anders Krogh, Jun Wang, Bo Torben Porse

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.
OriginalsprogEngelsk
TidsskriftGenome Biology (Online Edition)
Vol/bind13
Tidsskriftsnummer5
Antal sider19
ISSN1474-760X
DOI
StatusUdgivet - 2012

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