title: Epigenomic Co-localization and Co-evolution Reveal a Key Role for 5hmC as a Communication Hub in the Chromatin Network of ESCs.
abstract: Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation. Notably, we found that 5-hydroxymethylcytosine (5hmC) is the most-influential hub of this network, connecting DNA demethylation to nucleosome remodeling complexes and to key transcription factors of pluripotency. Moreover, an evolutionary analysis revealed a central role of 5hmC in the co-evolution of chromatin-related proteins. Further analysis of regions where 5hmC co-localizes with specific interactors shows that each interaction points to chromatin remodeling, stemness, differentiation, or metabolism. Our results highlight the importance of cytosine modifications in the epigenetic communication of ESCs.
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Juan
authors.affiliation: Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Perner
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Carrillo de Santa Pau
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Simone
authors.initials: S
authors.lastname: Marsili
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ochoa
authors.affiliation: Otto-Warburg-Laboratories Epigenomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Ho-Ryun
authors.initials: HR
authors.lastname: Chung
authors.affiliation: Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Electronic address: drico@cnio.es.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Center - CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Electronic address: valencia@cnio.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002843:Chromatin; D046912:Multiprotein Complexes; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine