title: A unique epigenetic signature is associated with active DNA replication loci in human embryonic stem cells.
abstract: The cellular epigenetic landscape changes as pluripotent stem cells differentiate to somatic cells or when differentiated cells transform to a cancerous state. These epigenetic changes are commonly correlated with differences in gene expression. Whether active DNA replication is also associated with distinct chromatin environments in these developmentally and phenotypically diverse cell types has not been known. Here, we used BrdU-seq to map active DNA replication loci in human embryonic stem cells (hESCs), normal primary fibroblasts and a cancer cell line, and correlated these maps to the epigenome. In all cell lines, the majority of BrdU peaks were enriched in euchromatin and at DNA repetitive elements, especially at microsatellite repeats, and coincided with previously determined replication origins. The most prominent BrdU peaks were shared between all cells but a sizable fraction of the peaks were specific to each cell type and associated with cell type-specific genes. Surprisingly, the BrdU peaks that were common to all cell lines were associated with H3K18ac, H3K56ac, and H4K20me1 histone marks only in hESCs but not in normal fibroblasts or cancer cells. Depletion of the histone acetyltransferases for H3K18 and H3K56 dramatically decreased the number and intensity of BrdU peaks in hESCs. Our data reveal a unique epigenetic signature that distinguishes active replication loci in hESCs from normal somatic or malignant cells.
authors.affiliation: Department of Biological Chemistry; University of California; Los Angeles, CA USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biological Chemistry; University of California; Los Angeles, CA USA; Division of Oral Biology and Medicine; School of Dentistry; University of California; Los Angeles, CA USA.
authors.forename: Trent
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of Biological Chemistry; University of California; Los Angeles, CA USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research; David Geffen School of Medicine; University of California; Los Angeles, CA USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Biological Chemistry; University of California; Los Angeles, CA USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research; David Geffen School of Medicine; University of California; Los Angeles, CA USA.
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Li
authors.affiliation: Department of Biological Chemistry; University of California; Los Angeles, CA USA; Molecular Biology Institute; University of California; Los Angeles, CA USA; Department of Pathology and Laboratory Medicine; University of California; Los Angeles, CA USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research; David Geffen School of Medicine; University of California; Los Angeles, CA USA.
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D056426:Genetic Loci; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D018741:Replication Origin
chemical_list: D006657:Histones; D004247:DNA; D051548:Histone Acetyltransferases
keywords: CBP; DNA replication; P300; chromatin; embryonic stem cells; epigenetics; histone acetyltransferase; histone modifications