title: Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization.
abstract: BACKGROUND
  Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata.
  
  
  RESULTS
  Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1.
  
  
  CONCLUSIONS
  We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK. ben.moore@igmm.ed.ac.uk.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Moore
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK. stuart.aitken@igmm.ed.ac.uk.
authors.forename: Stuart
authors.initials: S
authors.lastname: Aitken
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK. colin.semple@igmm.ed.ac.uk.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
mesh_terms: D000076246:CCCTC-Binding Factor; D002460:Cell Line; D002843:Chromatin / Q000235:genetics*; D042522:DNA Replication Timing; D004268:DNA-Binding Proteins / Q000235:genetics; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D056426:Genetic Loci; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D005810:Multigene Family; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D012097:Repressor Proteins