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Regulatory Divergence of Transcript Isoforms in a Mammalian Model System

Leigh-Brown, Sarah and Goncalves, Angela and Thybert, David and Stefflova, Klara and Watt, Stephen and Flicek, Paul and Brazma, Alvis and Marioni, John C. and Odom, Duncan T. (2015) Regulatory Divergence of Transcript Isoforms in a Mammalian Model System. PLoS ONE, 10 (9). Art. No. e0137367. ISSN 1932-6203. PMCID PMC4560434. http://resolver.caltech.edu/CaltechAUTHORS:20150925-085736543

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[img] Image (TIFF) (S2 Fig. Expression level and MCSEs) - Supplemental Material
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Abstract

Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pone.0137367DOIArticle
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137367PublisherArticle
http://dx.doi.org/10.1371/journal.pone.0137367.s001DOIS1 Fig. Model Selection
http://dx.doi.org/10.1371/journal.pone.0137367.s002DOIS2 Fig. Expression level and MCSEs
http://dx.doi.org/10.1371/journal.pone.0137367.s003DOIS3 Fig. Validation in an in silico F1 dataset
http://dx.doi.org/10.1371/journal.pone.0137367.s004DOIS4 Fig. Extrapolation to genes with many >2 isoforms
http://dx.doi.org/10.1371/journal.pone.0137367.s005DOIS1 Table. Table of all genes expressing 2 isoforms in adult mouse liver
http://dx.doi.org/10.1371/journal.pone.0137367.s006DOIS2 Table. Table of regions targeted for pyrosequencing validation
http://dx.doi.org/10.1371/journal.pone.0137367.s007DOIS3 Table. Table of known regulators of splicing assessed for differential expression in mouse liver
http://dx.doi.org/10.1371/journal.pone.0137367.s008DOIS4 Table. Enrichment of known splice regulator motifs in genes with divergent isoform usage
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560434/PubMed CentralArticle
Additional Information:© 2015 Leigh-Brown et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 9, 2015; Accepted: August 15, 2015; Published: September 4, 2015. Funding: This work was supported by the European Research Council (DTO) (http://erc.europa.eu/); EMBO Young Investigators Program (DTO) (http://www.embo.org/funding-awards/young-investigators); Hutchinson Whampoa (DTO) (http://www.hutchisonwhampoa. com/en/global/home.php); Cancer Research UK (DTO, SLB, KS, SW) (http://www.cancerresearchuk.org/); University of Cambridge (SLB, KS, DTO, AG) (http://www.cam.ac.uk/); European Molecular Biology Laboratory (AG, DT, AB, PF, JCM) (http://www.embl.org/); Wellcome Trust WT095908 and WT098051 (DT, PF, DTO) (http://www.wellcome.ac.uk/); and FP7 HEALTH grant from the European Commission GEUVADIS grant agreement 261123 (AG, AB) (http://www.geuvadis.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Since performing the experimental work and writing this manuscript, SLB has taken paid employment at Abcam, a Biotech firm selling reagents to research scientists. Abcam had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Since performing the experimental work and writing this manuscript, SLB has taken paid employment at Abcam, a Biotech firm selling reagents to research scientists. Abcam have no interest in the submitted manuscript and NO Abcam products were used for this experimental work. The authors do not consider this to be a competing interest, and the authors declare it here so that the reviewers may be fully informed. We thank CRUK-CI Genomics, Bioinformatics and Biological Resources Facilities plus Barts and The London Genome Centre for their expertise and involvement in this study. We are grateful to David Adams (Wellcome Trust Sanger Institute) for prior access to the genome and transcriptome sequences for the mouse strains used in this study. We also acknowledge helpful comments and suggestions from Ernest Turro, Simon Anders, Wolfgang Huber, Jenny Tung, Luis Barreiro, Athma Pai, Yoav Gilad, and members of the Marioni, Odom, Flicek, and Brazma groups. Author Contributions: Conceived and designed the experiments: DTO JCM SLB AG KS DT. Performed the experiments: SLB SW. Analyzed the data: AG JCM DT SLB AB. Contributed reagents/materials/analysis tools: PF DT KS AB. Wrote the paper: SLB AG JCM DTO. Provided Castaneus genome: PF. Generated Castaneus transcriptome: DT.
Funders:
Funding AgencyGrant Number
European Research Council (ERC)UNSPECIFIED
European Molecular Biology Organization (EMBO)UNSPECIFIED
Hutchinson WhampoaUNSPECIFIED
Cancer Research UKUNSPECIFIED
University of CambridgeUNSPECIFIED
European Molecular Biology LaboratoryUNSPECIFIED
Wellcome TrustWT095908
Wellcome TrustWT098051
European Commission FP7 HEALTH261123
PubMed Central ID:PMC4560434
Record Number:CaltechAUTHORS:20150925-085736543
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20150925-085736543
Official Citation:Leigh-Brown S, Goncalves A, Thybert D, Stefflova K, Watt S, Flicek P, et al. (2015) Regulatory Divergence of Transcript Isoforms in a Mammalian Model System. PLoS ONE 10(9): e0137367. doi:10.1371/journal.pone.0137367
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60506
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Sep 2015 16:22
Last Modified:25 Sep 2015 16:25

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