title: Combinatorial Histone Acetylation Patterns Are Generated by Motif-Specific Reactions.
abstract: Post-translational modifications (PTMs) are pivotal to cellular information processing, but how combinatorial PTM patterns ("motifs") are set remains elusive. We develop a computational framework, which we provide as open source code, to investigate the design principles generating the combinatorial acetylation patterns on histone H4 in Drosophila melanogaster. We find that models assuming purely unspecific or lysine site-specific acetylation rates were insufficient to explain the experimentally determined motif abundances. Rather, these abundances were best described by an ensemble of models with acetylation rates that were specific to motifs. The model ensemble converged upon four acetylation pathways; we validated three of these using independent data from a systematic enzyme depletion study. Our findings suggest that histone acetylation patterns originate through specific pathways involving motif-specific acetylation activity.
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Center for Mathematics, 85748 Garching, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blasi
authors.affiliation: Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität, 82152 Planegg, Germany. Electronic address: feller@imsb.biol.ethz.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Feller
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Center for Mathematics, 85748 Garching, Germany.
authors.forename: Justin
authors.initials: J
authors.lastname: Feigelman
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Center for Mathematics, 85748 Garching, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hasenauer
authors.affiliation: Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität, 82152 Planegg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Center for Mathematics, 85748 Garching, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität, 82152 Planegg, Germany.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Becker
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: carsten.marr@helmholtz-muenchen.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Marr
mesh_terms: D000107:Acetylation; D000818:Animals; D004331:Drosophila melanogaster; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones