title: Annotation of genomics data using bidirectional hidden Markov models unveils variations in Pol II transcription cycle.
abstract: DNA replication, transcription and repair involve the recruitment of protein complexes that change their composition as they progress along the genome in a directed or strand-specific manner. Chromatin immunoprecipitation in conjunction with hidden Markov models (HMMs) has been instrumental in understanding these processes, as they segment the genome into discrete states that can be related to DNA-associated protein complexes. However, current HMM-based approaches are not able to assign forward or reverse direction to states or properly integrate strand-specific (e.g., RNA expression) with non-strand-specific (e.g., ChIP) data, which is indispensable to accurately characterize directed processes. To overcome these limitations, we introduce bidirectional HMMs which infer directed genomic states from occupancy profiles de novo. Application to RNA polymerase II-associated factors in yeast and chromatin modifications in human T cells recovers the majority of transcribed loci, reveals gene-specific variations in the yeast transcription cycle and indicates the existence of directed chromatin state patterns at transcribed, but not at repressed, regions in the human genome. In yeast, we identify 32 new transcribed loci, a regulated initiation-elongation transition, the absence of elongation factors Ctk1 and Paf1 from a class of genes, a distinct transcription mechanism for highly expressed genes and novel DNA sequence motifs associated with transcription termination. We anticipate bidirectional HMMs to significantly improve the analyses of genome-associated directed processes.
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Zacher
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lidschreiber
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cramer
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany tresch@mpipz.mpg.de gagneur@genzentrum.lmu.de.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.affiliation: Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Institute for Genetics, University of Cologne, Cologne, Germany Max Planck Institute for Plant Breeding Research, Cologne, Germany tresch@mpipz.mpg.de gagneur@genzentrum.lmu.de.
authors.forename: Achim
authors.initials: A
authors.lastname: Tresch
mesh_terms: D047369:Chromatin Immunoprecipitation; D030541:Databases, Genetic; D005786:Gene Expression Regulation; D056426:Genetic Loci; D014644:Genetic Variation; D016681:Genome, Fungal; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D008390:Markov Chains; D008962:Models, Theoretical; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D012319:RNA Polymerase II
keywords: RNA transcription cycle; bidirectional hidden Markov model; chromatin marks; genome annotation