title: Nucleosome Organization in Human Embryonic Stem Cells.
abstract: The fundamental repeating unit of eukaryotic chromatin is the nucleosome. Besides being involved in packaging DNA, nucleosome organization plays an important role in transcriptional regulation and cellular identity. Currently, there is much debate about the major determinants of the nucleosome architecture of a genome and its significance with little being known about its role in stem cells. To address these questions, we performed ultra-deep sequencing of nucleosomal DNA in two human embryonic stem cell lines and integrated our data with numerous epigenomic maps. Our analyses have revealed that the genome is a determinant of nucleosome organization with transcriptionally inactive regions characterized by a "ground state" of nucleosome profiles driven by underlying DNA sequences. DNA sequence preferences are associated with heterogeneous chromatin organization around transcription start sites. Transcription, histone modifications, and DNA methylation alter this "ground state" by having distinct effects on both nucleosome positioning and occupancy. As the transcriptional rate increases, nucleosomes become better positioned. Exons transcribed and included in the final spliced mRNA have distinct nucleosome profiles in comparison to exons not included at exon-exon junctions. Genes marked by the active modification H3K4m3 are characterized by lower nucleosome occupancy before the transcription start site compared to genes marked by the inactive modification H3K27m3, while bivalent domains, genes associated with both marks, lie exactly in the middle. Combinatorial patterns of epigenetic marks (chromatin states) are associated with unique nucleosome profiles. Nucleosome organization varies around transcription factor binding in enhancers versus promoters. DNA methylation is associated with increasing nucleosome occupancy and different types of methylations have distinct location preferences within the nucleosome core particle. Finally, computational analysis of nucleosome organization alone is sufficient to elucidate much of the circuitry of pluripotency. Our results, suggest that nucleosome organization is associated with numerous genomic and epigenomic processes and can be used to elucidate cellular identity.
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Puya G
authors: PG
authors: Yazdi
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Brian A
authors: BA
authors: Pedersen
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Jared F
authors: JF
authors: Taylor
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America.
authors: Omar S
authors: OS
authors: Khattab
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Yu-Han
authors: YH
authors: Chen
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Yumay
authors: Y
authors: Chen
authors: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, United States of America; Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Steven E
authors: SE
authors: Jacobsen
authors: UC Irvine Diabetes Center, University of California Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California, United States of America; Department of Medicine, University of California Irvine, Irvine, California, United States of America; Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America; Department of Physiology & Biophysics, University of California Irvine, Irvine, California, United States of America.
authors: Ping H
authors: PH
authors: Wang
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D006657:Histones; D009707:Nucleosomes; D014157:Transcription Factors