title: An expansive human regulatory lexicon encoded in transcription factor footprints.
abstract: Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Neph
authors.forename: Jeff
authors.initials: J
authors.lastname: Vierstra
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Stergachis
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reynolds
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vernot
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.forename: Audra K
authors.initials: AK
authors.lastname: Johnson
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Maurano
authors.forename: Richard
authors.initials: R
authors.lastname: Humbert
authors.forename: Eric
authors.initials: E
authors.lastname: Rynes
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Shinny
authors.initials: S
authors.lastname: Vong
authors.forename: Kristen
authors.initials: K
authors.lastname: Lee
authors.forename: Daniel
authors.initials: D
authors.lastname: Bates
authors.forename: Morgan
authors.initials: M
authors.lastname: Diegel
authors.forename: Vaughn
authors.initials: V
authors.lastname: Roach
authors.forename: Douglas
authors.initials: D
authors.lastname: Dunn
authors.forename: Jun
authors.initials: J
authors.lastname: Neri
authors.forename: Anthony
authors.initials: A
authors.lastname: Schafer
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hansen
authors.forename: Tanya
authors.initials: T
authors.lastname: Kutyavin
authors.forename: Erika
authors.initials: E
authors.lastname: Giste
authors.forename: Molly
authors.initials: M
authors.lastname: Weaver
authors.forename: Theresa
authors.initials: T
authors.lastname: Canfield
authors.forename: Peter
authors.initials: P
authors.lastname: Sabo
authors.forename: Miaohua
authors.initials: M
authors.lastname: Zhang
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balasundaram
authors.forename: Rachel
authors.initials: R
authors.lastname: Byron
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacCoss
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: M A
authors.initials: MA
authors.lastname: Bender
authors.forename: Mark
authors.initials: M
authors.lastname: Groudine
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
mesh_terms: 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; D015894:Genome, Human / Q000235:genetics*; D018392:Genomic Imprinting; D023281:Genomics; D006801:Humans; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA; D003850:Deoxyribonuclease I