title: Determination and inference of eukaryotic transcription factor sequence specificity.
abstract: Transcription factor (TF) DNA sequence preferences direct their regulatory activity, but are currently known for only ∼1% of eukaryotic TFs. Broadly sampling DNA-binding domain (DBD) types from multiple eukaryotic clades, we determined DNA sequence preferences for >1,000 TFs encompassing 54 different DBD classes from 131 diverse eukaryotes. We find that closely related DBDs almost always have very similar DNA sequence preferences, enabling inference of motifs for ∼34% of the ∼170,000 known or predicted eukaryotic TFs. Sequences matching both measured and inferred motifs are enriched in chromatin immunoprecipitation sequencing (ChIP-seq) peaks and upstream of transcription start sites in diverse eukaryotic lineages. SNPs defining expression quantitative trait loci in Arabidopsis promoters are also enriched for predicted TF binding sites. Importantly, our motif "library" can be used to identify specific TFs whose binding may be altered by human disease risk alleles. These data present a powerful resource for mapping transcriptional networks across eukaryotes.
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Ally
authors.initials: A
authors.lastname: Yang
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Mihai
authors.initials: M
authors.lastname: Albu
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Atina G
authors.initials: AG
authors.lastname: Cote
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Montenegro-Montero
authors.affiliation: Computational Biology Center, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Drewe
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Hamed S
authors.initials: HS
authors.lastname: Najafabadi
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto ON M5S 1A8, Canada.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Lambert
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Ishminder
authors.initials: I
authors.lastname: Mann
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto ON M5S 1A8, Canada.
authors.forename: Kate
authors.initials: K
authors.lastname: Cook
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Goity
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada; Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: van Bakel
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 7621, CNRS, Laboratoire d'Océanographie Microbienne, Observatoire Océanologique, F-66650 Banyuls/mer, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lozano
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Galli
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Plant Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Mathew G
authors.initials: MG
authors.lastname: Lewsey
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eryong
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Electronic and Computing Systems, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Tuhin
authors.initials: T
authors.lastname: Mukherjee
authors.affiliation: Department of Electronic and Computing Systems, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Reece-Hoyes
authors.affiliation: DNA2.0 Inc., Menlo Park, CA 94025, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Shaulsky
authors.affiliation: Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Albertha J M
authors.initials: AJM
authors.lastname: Walhout
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 7621, CNRS, Laboratoire d'Océanographie Microbienne, Observatoire Océanologique, F-66650 Banyuls/mer, France.
authors.forename: François-Yves
authors.initials: FY
authors.lastname: Bouget
authors.affiliation: Computational Biology Center, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Ratsch
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Larrondo
authors.affiliation: Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Plant Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
authors.affiliation: Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto ON M5S 1A8, Canada. Electronic address: t.hughes@utoronto.ca.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
mesh_terms: D017360:Arabidopsis / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D006801:Humans; D059372:Nucleotide Motifs; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors