title: Developmental fate and cellular maturity encoded in human regulatory DNA landscapes.
abstract: Cellular-state information between generations of developing cells may be propagated via regulatory regions. We report consistent patterns of gain and loss of DNase I-hypersensitive sites (DHSs) as cells progress from embryonic stem cells (ESCs) to terminal fates. DHS patterns alone convey rich information about cell fate and lineage relationships distinct from information conveyed by gene expression. Developing cells share a proportion of their DHS landscapes with ESCs; that proportion decreases continuously in each cell type as differentiation progresses, providing a quantitative benchmark of developmental maturity. Developmentally stable DHSs densely encode binding sites for transcription factors involved in autoregulatory feedback circuits. In contrast to normal cells, cancer cells extensively reactivate silenced ESC DHSs and those from developmental programs external to the cell lineage from which the malignancy derives. Our results point to changes in regulatory DNA landscapes as quantitative indicators of cell-fate transitions, lineage relationships, and dysfunction.
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Andrew B
authors: AB
authors: Stergachis
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Shane
authors: S
authors: Neph
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Alex
authors: A
authors: Reynolds
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Richard
authors: R
authors: Humbert
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.|Department of Medicine, Division of Hematology University of Washington, Seattle, WA 98195, USA.
authors: Brady
authors: B
authors: Miller
authors: Department of Pathology, University of Washington, Seattle, WA 98109, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
authors: Sharon L
authors: SL
authors: Paige
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Benjamin
authors: B
authors: Vernot
authors: Department of Dermatology, University of California, San Francisco, CA 94143, USA.
authors: Jeffrey B
authors: JB
authors: Cheng
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Robert E
authors: RE
authors: Thurman
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Richard
authors: R
authors: Sandstrom
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Eric
authors: E
authors: Haugen
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Shelly
authors: S
authors: Heimfeld
authors: Department of Pathology, University of Washington, Seattle, WA 98109, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.|Department of Bioengineering, University of Washington, Seattle, WA 98109, USA.|Department of Medicine, Division of Cardiology University of Washington, Seattle, WA 98195, USA.
authors: Charles E
authors: CE
authors: Murry
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
authors: Joshua M
authors: JM
authors: Akey
authors: Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.|Department of Medicine, Division of Oncology University of Washington, Seattle, WA 98195, USA.
authors: John A
authors: JA
authors: Stamatoyannopoulos
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005246:Feedback; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D013234:Stem Cells / Q000378:metabolism
chemical_list: D002843:Chromatin
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