Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 6, Pages 708-U108Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2059
Keywords
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Funding
- Spanish Ministerio de Ciencia e Innovacion (MICINN) [BFU2007-60042/BMC, BFU2010-14839, Petri PET2007_0158, CONSOLIDER CSD2007-00008, BFU2009-07044, PN-SAF2009-11491, BFU2008-00838, BFU2006-12185, BIO2009-12697, BIO2006-03380, CONSOLIDER CSD2007-00050]
- Proyecto de Excelencia (Junta de Andalucia) [CVI-3488, CVI 2658, P07-CVI-02551]
- FIS (ISCIII) [PI081636]
- Regional Government of Madrid [CAM S-SAL-0190-2006]
- Pro-CNIC Foundation
- Direccion General de Asuntos del Personal Academico, Universidad Nacional Autonoma de Mexico [IN209403, IN214407, IN203811]
- Consejo Nacional de Ciencia y Tecnologia, Mexico (CONACyT) [42653-Q, 58767, 128464]
- US NCBI (NIH)
- Spanish MICINN [RETICS RD07/0067/0012]
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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.
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