title: Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association.
abstract: Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to identify quantitative trait loci (QTLs) that influence the binding of a transcription factor in humans, we measured binding of the multifunctional transcription and chromatin factor CTCF in 51 HapMap cell lines. We identified thousands of QTLs in which genotype differences were associated with differences in CTCF binding strength, hundreds of them confirmed by directly observable allele-specific binding bias. The majority of QTLs were either within 1 kb of the CTCF binding motif, or in linkage disequilibrium with a variant within 1 kb of the motif. On the X chromosome we observed three classes of binding sites: a minority class bound only to the active copy of the X chromosome, the majority class bound to both the active and inactive X, and a small set of female-specific CTCF sites associated with two non-coding RNA genes. In sum, our data reveal extensive genetic effects on CTCF binding, both direct and indirect, and identify a diversity of patterns of CTCF binding on the X chromosome.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Ni
authors.affiliation: The European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Sander W
authors.initials: SW
authors.lastname: Timmer
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Battenhouse
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Louzada
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.affiliation: The European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.affiliation: Institute for Genome Sciences and Policy, and Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, United States of America.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: Department of Biology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Iyer
authors.affiliation: The European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
mesh_terms: D000483:Alleles; D000076246:CCCTC-Binding Factor; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D011485:Protein Binding; D040641:Quantitative Trait Loci; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D022661:RNA, Untranslated; D012097:Repressor Proteins