title: Distinct epigenetic features of differentiation-regulated replication origins.
abstract: BACKGROUND
  Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status.
  
  
  RESULTS
  To identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types. Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions. Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. The first origin group consisted of about 40,000 regions that actively initiated replication in all cell types and preferentially colocalized with unmethylated CpGs and with the euchromatin markers, H3K4me3 and H3K9Ac. The second group included origins that were consistently active in cells of a single type or lineage and preferentially colocalized with the heterochromatin marker, H3K9me3. Shared origins replicated throughout the S-phase of the cell cycle, whereas cell-type-specific origins preferentially replicated during late S-phase.
  
  
  CONCLUSIONS
  These observations are in line with the hypothesis that differentiation-associated changes in chromatin and gene expression affect the activation of specific replication origins.
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Owen K
authors.initials: OK
authors.lastname: Smith
authors.affiliation: In Silico Solutions, Falls Church, VA 22033 USA.
authors.forename: RyanGuk
authors.initials: R
authors.lastname: Kim
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Fu
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Melvenia M
authors.initials: MM
authors.lastname: Martin
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Chii Mei
authors.initials: CM
authors.lastname: Lin
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Utani
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Marks
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06032 USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Lalande
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06032 USA.
authors.forename: Stormy
authors.initials: S
authors.lastname: Chamberlain
authors.affiliation: Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195 USA.
authors.forename: Maxwell W
authors.initials: MW
authors.lastname: Libbrecht
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
authors.affiliation: In Silico Solutions, Falls Church, VA 22033 USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ryan
authors.affiliation: Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195 USA ; Department of Genome Sciences, University of Washington, Seattle, WA 98195 USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Noble
authors.affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Mirit I
authors.initials: MI
authors.lastname: Aladjem
keywords: Cell cycle; Cellular differentiation; Chromatin; CpG islands; H3K4me3; H3K9Ac; H3K9me3; Histone modification; Origin of replication; Proliferation