title: Detecting translational regulation by change point analysis of ribosome profiling data sets.
abstract: Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While during normal translation, ribosome density is constant along the length of the mRNA coding region, this can be altered in response to translational regulatory events. In the present study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modeling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq data set obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artifacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g., premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new transcript isoforms.
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, NE4 5PL, United Kingdom Department of Environmental Toxicology, Eawag: Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, Switzerland daryl.shanley@ncl.ac.uk anze.zupanic@eawag.ch.
authors.forename: Anze
authors.initials: A
authors.lastname: Zupanic
authors.affiliation: Institute for Cell and Molecular Biosciences and Human Nutrition Research Centre, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Meplan
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, United Kingdom.
authors.forename: Sushma N
authors.initials: SN
authors.lastname: Grellscheid
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, NE4 5PL, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, NE4 5PL, United Kingdom.
authors.forename: Tom B L
authors.initials: TB
authors.lastname: Kirkwood
authors.affiliation: Institute for Cell and Molecular Biosciences and Human Nutrition Research Centre, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Hesketh
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, NE4 5PL, United Kingdom daryl.shanley@ncl.ac.uk anze.zupanic@eawag.ch.
authors.forename: Daryl P
authors.initials: DP
authors.lastname: Shanley
mesh_terms: D000465:Algorithms; D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D008962:Models, Theoretical; D011132:Polyribosomes / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger
keywords: change point analysis; mathematical modeling; ribosome profiling; translation regulation