title: Bioinformatic and proteomic analysis of bulk histones reveals PTM crosstalk and chromatin features.
abstract: Systems analysis of chromatin has been constrained by complex patterns and dynamics of histone post-translational modifications (PTMs), which represent major challenges for both mass spectrometry (MS) and immuno-based approaches (e.g., chromatin immuno-precipitation, ChIP). Here we present a proof-of-concept study demonstrating that crosstalk among PTMs and their functional significance can be revealed via systematic bioinformatic and proteomic analysis of steady-state histone PTM levels from cells under various perturbations. Using high resolution tandem MS, we quantified 53 modification states from all core histones and their conserved variants in the unicellular eukaryotic model organism Tetrahymena. By correlating histone PTM patterns across 15 different conditions, including various physiological states and mutations of key histone modifying enzymes, we identified 5 specific chromatin states with characteristic covarying histone PTMs and associated them with distinctive functions in replication, transcription, and DNA repair. In addition to providing a detailed picture on histone PTM crosstalk at global levels, this work has established a novel bioinformatic and proteomic approach, which can be adapted to other organisms and readily scaled up to allow increased resolution of chromatin states.
authors.affiliation: Departments of †Computational Medicine and Bioinformatics, ‡Pathology, ∥Chemistry, and ⊥Biological Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Chunchao
authors.initials: C
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Molascon
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Martin A
authors.initials: MA
authors.lastname: Gorovsky
authors.forename: Yifan
authors.initials: Y
authors.lastname: Liu
authors.forename: Philip C
authors.initials: PC
authors.lastname: Andrews
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D002843:Chromatin / Q000378:metabolism*; D019295:Computational Biology; D044127:Epigenesis, Genetic; D006657:Histones; D008745:Methylation; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015800:Protozoan Proteins / Q000378:metabolism*; D016808:Tetrahymena thermophila
chemical_list: D002843:Chromatin; D006657:Histones; D020543:Proteome; D015800:Protozoan Proteins