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

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

96 Citationer (Scopus)
2829 Downloads (Pure)

Abstract

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
Udgave nummer5
Antal sider19
ISSN1474-7596
DOI
StatusUdgivet - 2012

Citationsformater