title: Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.
abstract: To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Vierstra
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Rynes
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Miaohua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Canfield
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hansen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Stehling-Sun
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Byron
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Humbert
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Audra K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shinny
authors.initials: S
authors.lastname: Vong
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bates
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Fidencio
authors.initials: F
authors.lastname: Neri
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Diegel
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Giste
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Dunn
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Wilken
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Howard Hughes Medical Institute.
authors.forename: Steven
authors.initials: S
authors.lastname: Josefowicz
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Howard Hughes Medical Institute.
authors.forename: Robert
authors.initials: R
authors.lastname: Samstein
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kai-Hsin
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Marella
authors.initials: M
authors.lastname: De Bruijn
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Reh
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Skoultchi
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Howard Hughes Medical Institute.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rudensky
authors.affiliation: Howard Hughes Medical Institute. Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Radiation Oncology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Groudine
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Bender
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 98195, USA. jstam@uw.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics*; D003850:Deoxyribonuclease I; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D051379:Mice; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D015183:Restriction Mapping; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D004247:DNA; D003850:Deoxyribonuclease I