{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Weischenfeldt J"],"funding":["European Research Council"],"pagination":["R35"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3446288"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(5)"],"pubmed_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."],"journal":["Genome biology"],"pubmed_title":["Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns."],"pmcid":["PMC3446288"],"funding_grant_id":["204135"],"pubmed_authors":["Porse BT","Krogh A","Waage J","Tian G","Damgaard I","Kristiansen K","Jakobsen JS","Weischenfeldt J","Zhao J","Wang J"],"additional_accession":[]},"is_claimable":false,"name":"Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns.","description":"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.","dates":{"release":"2012-01-01T00:00:00Z","publication":"2012","modification":"2020-11-19T12:06:24Z","creation":"2019-03-27T00:58:07Z"},"accession":"S-EPMC3446288","cross_references":{"pubmed":["22624609"],"doi":["10.1186/gb-2012-13-5-r35"]}}