title: Conservation of trans-acting circuitry during mammalian regulatory evolution.
abstract: The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Stergachis
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Neph
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reynolds
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Miaohua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Byron
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Canfield
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Stelhing-Sun
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Shinny
authors.initials: S
authors.lastname: Vong
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bates
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Fidencio
authors.initials: F
authors.lastname: Neri
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Diegel
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Giste
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Dunn
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Vierstra
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hansen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Audra K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Wilken
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Reh
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.affiliation: 1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Division of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Groudine
authors.affiliation: 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Bender
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98102, USA [3] Santa Fe Institute, Santa Fe, New Mexico 87501, USA.
authors.forename: Elhanan
authors.initials: E
authors.lastname: Borenstein
authors.affiliation: 1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
mesh_terms: D000818:Animals; D017124:Conserved Sequence / Q000235:genetics*; D018983:DNA Footprinting; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008322:Mammals / Q000235:genetics*; D051379:Mice; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014157:Transcription Factors