Journal Article

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

Recillas-Targa, Félix, Casares, Fernando, Ovcharenko, Ivan, Serrano, Manuel, Pantoja, Cristina, Alcina, Antonio, Martin, David, de la Calle-Mustienes, Elisa, Cañón, Susana, Guigó, Roderic, Gómez-Skarmeta, José Luis, Taher, Leila, Matesanz, Fuencisla, Montoliu, Lluís, Miñán, Ana Fernández, Domínguez, Orlando, Blasco, María A, Manzanares, Miguel, Bogdanović, Ozren, Furlan-Magaril, Mayra, Valdes-Quezada, Christian, Fedetz, María, Moltó, Eduardo, Pereira, Paulo S

2011

Overview

Identifying genes associated with SNPs in non-coding regions is difficult as the SNPs are often located far from the promoters they impact. Cross-species comparison of sites occupied by the insulating protein CTCF reveals conserved boundaries between genes often associated with disease. Multiple sclerosis–associated SNPs occur in the GFI1-EVI5 genomic region near several constitutively bound CTCF sites, enabling the authors to propose GFI1 as the gene linked to MS instead of the previously suggested EVI5 . 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 .

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 692/699/375/1666 / Animals / Autoimmune diseases / Biochemistry / Biological Microscopy / Biomedical and Life Sciences / Boundaries / CCCTC-Binding Factor / Cell Cycle Proteins / Cell Line / Cellular biology / Chickens / Conserved Sequence / DNA - metabolism / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Gene expression / Genome / Genomes / Genomics / GTPase-Activating Proteins / Humans / Life Sciences / Mammals / Membrane Biology / Mice / Molecular biology / Multiple sclerosis / Multiple Sclerosis - pathology / Mutation / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Polymorphism, Genetic / Protein Binding / Protein Structure / Proteins / Repressor Proteins - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism