title: Considering the kinetics of mRNA synthesis in the analysis of the genome and epigenome reveals determinants of co-transcriptional splicing.
abstract: When messenger RNA splicing occurs co-transcriptionally, the potential for kinetic control based on transcription dynamics is widely recognized. Indeed, perturbation studies have reported that when transcription kinetics are perturbed genetically or pharmacologically splice patterns may change. However, whether kinetic control is contributing to the control of splicing within the normal range of physiological conditions remains unknown. We examined if the kinetic determinants for co-transcriptional splicing (CTS) might be reflected in the structure and expression patterns of the genome and epigenome. To identify and then quantitatively relate multiple, simultaneous CTS determinants, we constructed a scalable mathematical model of the kinetic interplay of RNA synthesis and CTS and parameterized it with diverse next generation sequencing (NGS) data. We thus found a variety of CTS determinants encoded in vertebrate genomes and epigenomes, and that these combine variously for different groups of genes such as housekeeping versus regulated genes. Together, our findings indicate that the kinetic basis of splicing is functionally and physiologically relevant, and may meaningfully inform the analysis of genomic and epigenomic data to provide insights that are missed when relying on statistical approaches alone.
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Davis-Turak
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Karmel
authors.initials: K
authors.lastname: Allison
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Shokhirev
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Ponomarenko
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA BioCircuits Institute, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Lev S
authors.initials: LS
authors.lastname: Tsimring
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, CA 90095, USA ahoffmann@ucla.edu.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Johnson
authors.affiliation: San Diego Center for Systems Biology (SDCSB), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA BioCircuits Institute, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California at Los Angeles, Los Angeles, CA 90095, USA Institute for Quantitative and Computational Biosciences (QCB), University of California at Los Angeles, Los Angeles, CA 90095, USA ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D003198:Computer Simulation; D044127:Epigenesis, Genetic; D020043:Genes, Essential; D023281:Genomics; D006801:Humans; D007700:Kinetics; D051379:Mice; D008957:Models, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D012319:RNA Polymerase II