title: The accessible chromatin landscape of the human genome.
abstract: DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: Eric
authors.initials: E
authors.lastname: Rynes
authors.forename: Richard
authors.initials: R
authors.lastname: Humbert
authors.forename: Jeff
authors.initials: J
authors.lastname: Vierstra
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Maurano
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Sheffield
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Stergachis
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vernot
authors.forename: Kavita
authors.initials: K
authors.lastname: Garg
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.forename: Daniel
authors.initials: D
authors.lastname: Bates
authors.forename: Lisa
authors.initials: L
authors.lastname: Boatman
authors.forename: Theresa K
authors.initials: TK
authors.lastname: Canfield
authors.forename: Morgan
authors.initials: M
authors.lastname: Diegel
authors.forename: Douglas
authors.initials: D
authors.lastname: Dunn
authors.forename: Abigail K
authors.initials: AK
authors.lastname: Ebersol
authors.forename: Tristan
authors.initials: T
authors.lastname: Frum
authors.forename: Erika
authors.initials: E
authors.lastname: Giste
authors.forename: Audra K
authors.initials: AK
authors.lastname: Johnson
authors.forename: Ericka M
authors.initials: EM
authors.lastname: Johnson
authors.forename: Tanya
authors.initials: T
authors.lastname: Kutyavin
authors.forename: Bryan
authors.initials: B
authors.lastname: Lajoie
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.forename: Kristen
authors.initials: K
authors.lastname: Lee
authors.forename: Darin
authors.initials: D
authors.lastname: London
authors.forename: Dimitra
authors.initials: D
authors.lastname: Lotakis
authors.forename: Shane
authors.initials: S
authors.lastname: Neph
authors.forename: Fidencio
authors.initials: F
authors.lastname: Neri
authors.forename: Eric D
authors.initials: ED
authors.lastname: Nguyen
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Qu
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reynolds
authors.forename: Vaughn
authors.initials: V
authors.lastname: Roach
authors.forename: Alexias
authors.initials: A
authors.lastname: Safi
authors.forename: Minerva E
authors.initials: ME
authors.lastname: Sanchez
authors.forename: Amartya
authors.initials: A
authors.lastname: Sanyal
authors.forename: Anthony
authors.initials: A
authors.lastname: Shafer
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.forename: Shinny
authors.initials: S
authors.lastname: Vong
authors.forename: Molly
authors.initials: M
authors.lastname: Weaver
authors.forename: Yongqi
authors.initials: Y
authors.lastname: Yan
authors.forename: Zhancheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhuzhu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hansen
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Navas
authors.forename: George
authors.initials: G
authors.lastname: Stamatoyannopoulos
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Iyer
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
mesh_terms: D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D018983:DNA Footprinting; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004690:Encyclopedias as Topic; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D058977:Molecular Sequence Annotation; D059645:Mutation Rate; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA; D003850:Deoxyribonuclease I