title: Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.
abstract: As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ballester
authors.affiliation: Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Medina-Rivera
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Mar
authors.initials: M
authors.lastname: Gonzàlez-Porta
authors.affiliation: Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Carlucci
authors.affiliation: School of Electronic and Computing Systems, University of Cincinnati, Cincinnati, United States.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
authors.forename: Kyle
authors.initials: K
authors.lastname: Chessman
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Faure
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Australia.
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Goncalves
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kutter
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Margus
authors.initials: M
authors.lastname: Lukk
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Suraj
authors.initials: S
authors.lastname: Menon
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: William M
authors.initials: WM
authors.lastname: McLaren
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Klara
authors.initials: K
authors.lastname: Stefflova
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watt
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Australia.
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Marioni
authors.affiliation: Cancer Research UK-Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Duncan T
authors.initials: DT
authors.lastname: Odom
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008322:Mammals / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D009928:Organ Specificity; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors
keywords: cis regulatory module; dog; evolutionary biology; genomics; human; human biology; liver; macaque; medicine; molecular evolution; mouse; rat; transcription factors