Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association

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 multifunc...

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Published inPLoS genetics Vol. 10; no. 11; p. e1004798
Main Authors Ding, Zhihao, Ni, Yunyun, Timmer, Sander W., Lee, Bum-Kyu, Battenhouse, Anna, Louzada, Sandra, Yang, Fengtang, Dunham, Ian, Crawford, Gregory E., Lieb, Jason D., Durbin, Richard, Iyer, Vishwanath R., Birney, Ewan
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.11.2014
Public Library of Science (PLoS)
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ISSN1553-7404
1553-7390
1553-7404
DOI10.1371/journal.pgen.1004798

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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.
AbstractList 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.
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. We have systematically measured the effect of normal genetic variation present in a human population on the binding of a specific chromatin protein (CTCF) to DNA by measuring its binding in 51 human cell lines. We observed a large number of changes in protein binding that we can confidently attribute to genetic effects. The corresponding genetic changes are often clustered around the binding motif for CTCF, but only a minority are actually within the motif. Unexpectedly, we also find that at most binding sites on the X chromosome, CTCF binding occurs equally on both the X chromosomes in females at the same level as on the single X chromosome in males. This finding suggests that in general, CTCF binding is not subject to global dosage compensation, the process which equalizes gene expression levels from the two female X chromosomes and the single male X.
  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.
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.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.
Audience Academic
Author Dunham, Ian
Ding, Zhihao
Lee, Bum-Kyu
Durbin, Richard
Battenhouse, Anna
Birney, Ewan
Yang, Fengtang
Crawford, Gregory E.
Lieb, Jason D.
Louzada, Sandra
Timmer, Sander W.
Ni, Yunyun
Iyer, Vishwanath R.
AuthorAffiliation 1 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom
3 The European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom
2 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
5 Department of Biology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
4 Institute for Genome Sciences and Policy, and Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, United States of America
Georgia Institute of Technology, United States of America
AuthorAffiliation_xml – name: Georgia Institute of Technology, United States of America
– name: 1 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom
– name: 4 Institute for Genome Sciences and Policy, and Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, United States of America
– name: 5 Department of Biology and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
– name: 2 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
– name: 3 The European Molecular Biology Laboratory, The European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/25411781$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2014 Public Library of Science
2014 Ding et al 2014 Ding et al
2014 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Ding Z, Ni Y, Timmer SW, Lee B-K, Battenhouse A, Louzada S, et al. (2014) Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association. PLoS Genet 10(11): e1004798. doi:10.1371/journal.pgen.1004798
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– notice: 2014 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Ding Z, Ni Y, Timmer SW, Lee B-K, Battenhouse A, Louzada S, et al. (2014) Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association. PLoS Genet 10(11): e1004798. doi:10.1371/journal.pgen.1004798
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Conceived and designed the experiments: ID GEC JDL VRI RD EB. Performed the experiments: AB SL FY BKL. Analyzed the data: ZD YN SWT ID RD EB. Contributed reagents/materials/analysis tools: GEC JDL. Wrote the paper: ZD YN SWT ID RD VRI EB.
The authors have declared that no competing interests exist.
Current address: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
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SSID ssj0035897
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Snippet Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order to...
  Associating genetic variation with quantitative measures of gene regulation offers a way to bridge the gap between genotype and complex phenotypes. In order...
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Enrichment Source
StartPage e1004798
SubjectTerms Alleles
Biology and Life Sciences
CCCTC-Binding Factor
Chromosomes
Chromosomes, Human, X - genetics
Female
Females
Gender
Gene expression
Genomes
Genomics
Genotype & phenotype
Humans
Linkage Disequilibrium
Males
Physiological aspects
Protein Binding
Protein research
Proteins
Quantitative genetics
Quantitative Trait Loci
Repressor Proteins - genetics
Repressor Proteins - metabolism
RNA polymerase
RNA, Untranslated - genetics
RNA, Untranslated - metabolism
Studies
Transcription factors
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Title Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association
URI https://www.ncbi.nlm.nih.gov/pubmed/25411781
https://www.proquest.com/docview/1627072898
https://pubmed.ncbi.nlm.nih.gov/PMC4238955
https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004798&type=printable
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