title: Transcriptional regulation by histone modifications: towards a theory of chromatin re-organization during stem cell differentiation.
abstract: Chromatin-related mechanisms, as e.g. histone modifications, are known to be involved in regulatory switches within the transcriptome. Only recently, mathematical models of these mechanisms have been established. So far they have not been applied to genome-wide data. We here introduce a mathematical model of transcriptional regulation by histone modifications and apply it to data of trimethylation of histone 3 at lysine 4 (H3K4me3) and 27 (H3K27me3) in mouse pluripotent and lineage-committed cells. The model describes binding of protein complexes to chromatin which are capable of reading and writing histone marks. Molecular interactions of the complexes with DNA and modified histones create a regulatory switch of transcriptional activity. The regulatory states of the switch depend on the activity of histone (de-) methylases, the strength of complex-DNA-binding and the number of nucleosomes capable of cooperatively contributing to complex-binding. Our model explains experimentally measured length distributions of modified chromatin regions. It suggests (i) that high CpG-density facilitates recruitment of the modifying complexes in embryonic stem cells and (ii) that re-organization of extended chromatin regions during lineage specification into neuronal progenitor cells requires targeted de-modification. Our approach represents a basic step towards multi-scale models of transcriptional control during development and lineage specification.
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig, D-04107 Leipzig, Härtelstr. 16-18, Germany. binder@izbi.uni-leipzig.de
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.forename: Lydia
authors.initials: L
authors.lastname: Steiner
authors.forename: Jens
authors.initials: J
authors.lastname: Przybilla
authors.forename: Thimo
authors.initials: T
authors.lastname: Rohlf
authors.forename: Sonja
authors.initials: S
authors.lastname: Prohaska
authors.forename: Jörg
authors.initials: J
authors.lastname: Galle
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D018899:CpG Islands; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006657:Histones; D004247:DNA