title: Motif signatures in stretch enhancers are enriched for disease-associated genetic variants.
abstract: BACKGROUND
  Stretch enhancers (SEs) are large chromatin-defined regulatory elements that are at least 3,000 base pairs (bps) long, in contrast to the median enhancer length of 800 bps. SEs tend to be cell-type specific, regulate cell-type specific gene expression, and are enriched in disease-associated genetic variants in disease-relevant cell types. Transcription factors (TFs) can bind to enhancers to modulate enhancer activity, and their sequence specificity can be represented by motifs. We hypothesize motifs can provide a biological context for how genetic variants contribute to disease.
  
  
  RESULTS
  We integrated chromatin state, gene expression, and chromatin accessibility [measured as DNase I Hypersensitive Sites (DHSs)] maps across nine different cell types. Motif enrichment analyses of chromatin-defined enhancer sequences identify several known cell-type specific "master" factors. Furthermore, de novo motif discovery not only recovers many of these motifs, but also identifies novel non-canonical motifs, providing additional insight into TF binding preferences. Across the length of SEs, motifs are most enriched in DHSs, though relative enrichment is also observed outside of DHSs. Interestingly, we show that single nucleotide polymorphisms associated with diseases or quantitative traits significantly overlap motif occurrences located in SEs, but outside of DHSs.
  
  
  CONCLUSIONS
  These results reinforce the role of SEs in influencing risk for diseases and suggest an expanded regulatory functional role for motifs that occur outside highly accessible chromatin. Furthermore, the motif signatures generated here expand our understanding of the binding preference of well-characterized TFs.
authors.affiliation: Department of Computer Science, University of California, Irvine, Irvine, CA, 92697, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, 92697, USA.
authors.forename: Daniel X
authors.initials: DX
authors.lastname: Quang
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.affiliation: Departments of Computational Medicine and Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. scjp@umich.edu.
authors.forename: Stephen C J
authors.initials: SCJ
authors.lastname: Parker
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins