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Nature Structural and Molecular BiologyVolume 18, Issue 6, June 2011, Pages 708-714

Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes(Article)

  • Martin, D.,
  • Pantoja, C.,
  • Fernández-Miñán, A.,
  • Valdes-Quezada, C.,
  • Moltó, E.,
  • Matesanz, F.,
  • Bogdanović, O.,
  • De La Calle-Mustienes, E.,
  • Domínguez, O.,
  • Taher, L.,
  • Furlan-Magaril, M.,
  • Alcina, A.,
  • Cañóon, S.,
  • Fedetz, M.,
  • Blasco, M.A.,
  • Pereira, P.S.,
  • Ovcharenko, I.,
  • Recillas-Targa, F.,
  • Montoliu, L.,
  • Manzanares, M.,
  • Guiǵo, R.,
  • Serrano, M.,
  • Casares, F.,
  • Gómez-Skarmeta, J.L.
  • View Correspondence (jump link)
  • aCenter for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain
  • bCentro Nacional de Investigaciones Oncológicas, Madrid, Spain
  • cCentro Andaluz de Biología Del Desarrollo, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Pablo de Olavide (UPO), Seville, Spain
  • dInstituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de Méxic, México DF, Mexico
  • eDepartment of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
  • fCentro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
  • gInstituto de Parasitología y Biomedicina Lopez-Neyra, CSIC, Granada, Spain
  • hNational Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health (NIH), Bethesda, MD, United States
  • iCentro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
  • jInstituto de Biologia Molecular e Celular (IBMC), Universidade Do Porto, Oporto 4150-180, Portugal

Abstract

Many genomic alterations associated with human diseases localize in noncoding regulatory elements located far from the promoters they regulate, making it challenging to link noncoding mutations or risk-associated variants with target genes. The range of action of a given set of enhancers is thought to be defined by insulator elements bound by the 11 zinc-finger nuclear factor CCCTC-binding protein (CTCF). Here we analyzed the genomic distribution of CTCF in various human, mouse and chicken cell types, demonstrating the existence of evolutionarily conserved CTCF-bound sites beyond mammals. These sites preferentially flank transcription factor-encoding genes, often associated with human diseases, and function as enhancer blockers in vivo, suggesting that they act as evolutionarily invariant gene boundaries. We then applied this concept to predict and functionally demonstrate that the polymorphic variants associated with multiple sclerosis located within the EVI5 gene impinge on the adjacent gene GFI1. © 2011 Nature America, Inc. All rights reserved.

Indexed keywords

EMTREE drug terms:transcription factor CTCF
EMTREE medical terms:animal cellarticlecell typecontrolled studyenhancer regionevi5 genegenegene identificationgenetic associationgenetic conservationgenomicsgfi1 genehumanhuman cellmultiple sclerosisnonhumanpolymorphic locuspriority journalvertebrate
MeSH:AnimalsCell LineChickensConserved SequenceDNADNA-Binding ProteinsGenomeHumansMiceMultiple SclerosisNuclear ProteinsPolymorphism, GeneticProtein BindingRepressor ProteinsTranscription Factors
Species Index:MammaliaVertebrata

Chemicals and CAS Registry Numbers:

CCCTC-binding factor; DNA, 9007-49-2; DNA-Binding Proteins; EVI5 protein, human; GFI1 protein, human; Nuclear Proteins; Repressor Proteins; Transcription Factors

Funding details

Funding sponsor Funding number Acronym
National Institutes of Health
See opportunities
National Institutes of Health
See opportunities
U.S. National Library of Medicine
See opportunities
Ministerio de Ciencia y TecnologíaMICYT
CAM S-SAL-0190-2006
Ministerio de Ciencia e InnovaciónMICINN
Universidad Autónoma de MadridIN214407,IN209403,IN203811
Ministerio de Ciencia e InnovaciónMICINN
Instituto de Salud Carlos IIIBFU2008-00838,PN-SAF2009-11491,P07-CVI-02551
Consejo Nacional de Ciencia y Tecnología58767,42653-Q,128464
BFU2006-12185,BIO2009-12697
Junta de AndalucíaCVI 2658,BFU2009-07044,FIS PI081636
National Institutes of Health
See opportunities		RETICS RD07/0067/0012,CONSOLIDER CSD2007-00050,BIO2006-03380
CVI-3488

  • 1

    1Center for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain. 2Centro Nacional de Investigaciones Oncológicas, Madrid, Spain. 3Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas (CSIC)–Universidad Pablo de Olavide (UPO), Seville, Spain. 4Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, México DF, México. 5Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Madrid, Spain. 6Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 7Instituto de Parasitología y Biomedicina Lopez-Neyra, CSIC, Granada, Spain. 8National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health (NIH), Bethesda, Maryland, USA. 9Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. 10Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Oporto 4150-180, Portugal. 11These authors contributed equally to this work. Correspondence should be addressed to F.C. ([email protected]) or J.L.G.-S. ([email protected]).

  • 2

    This research was supported by the following grants: BFU2007-60042/BMC, BFU2010-14839, Petri PET2007_0158, CONSOLIDER CSD2007-00008 (Spanish Ministerio de Ciencia e Innovación (MICINN)) and Proyecto de Excelencia CVI-3488 (Junta de Andalucía) to J.L.G.-S.; BFU2009-07044 (MICINN) and Proyecto de Excelencia CVI 2658 (Junta de Andalucía) to F.C.; FIS PI081636 (ISCIII) to F.M.; PN-SAF2009-11491 (MICINN) and Proyecto de Excelencia P07-CVI-02551 (Junta de Andalucía) to A.A.; BFU2008-00838, CONSOLIDER CSD2007-00008 (MICINN), Regional Government of Madrid (CAM S-SAL-0190-2006) and the Pro-CNIC Foundation to M.M.; BFU2006-12185 and BIO2009-12697 (MICINN) to L.M.; Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México (IN209403, IN214407 and IN203811) and Consejo Nacional de Ciencia y Tecnología, México (CONACyT: 42653-Q, 58767 and 128464) to F.R.-T.; Intramural Research Program of the US NCBI (NIH) to I.O. and BIO2006-03380, CONSOLIDER CSD2007-00050 (MICINN) and RETICS RD07/0067/0012 (Spanish MICINN) to R.G. L.M. thanks A. Fernández for technical assistance and L. Barrios for statistical analysis. F.R.-T. thanks G.G. Avendaño for technical assistance.

  • ISSN: 15459993
  • CODEN: NSMBC
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1038/nsmb.2059
  • PubMed ID: 21602820
  • Document Type: Article

  Casares, F.; Centro Andaluz de Biología Del Desarrollo, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Pablo de Olavide (UPO), Spain;
© Copyright 2012 Elsevier B.V., All rights reserved. © MEDLINE® is the source for the MeSH terms of this document.

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