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

D. Martin, C. Pantoja, A. Fernández-Miñán, C. Valdes-Quezada, E. Moltó, F. Matesanz, Ozren Bogdanović, E. De La Calle-Mustienes, O. Domínguez, L. Taher, M. Furlan-Magaril, A. Alcina, S. Cañóon, M. Fedetz, M.A. Blasco, P.S. Pereira, I. Ovcharenko, F. Recillas-Targa, L. Montoliu, M. ManzanaresR. Guiǵo, M. Serrano, F. Casares, J.L. Gómez-Skarmeta

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)708-714
JournalNature Structural and Molecular Biology
Volume18
Issue number6
DOIs
Publication statusPublished - 2011

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