Patterns of regulatory activity across diverse human cell-types predict tissue identity, transcription factor binding, and long-range interactions
- Nathan C Sheffield1,
- Robert E Thurman2,
- Lingyun Song1,
- Alexias Safi1,
- John A Stamatoyannopoulos2,
- Boris Lenhard3,
- Gregory E Crawford1 and
- Terrence S Furey4,5
- 1 Duke University;
- 2 University of Washington;
- 3 Imperial College London;
- 4 University of North Carolina, Chapel Hill
- ↵* Corresponding author; email: tsfurey{at}email.unc.edu
Abstract
Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell-types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell-types. We first defined over 1,800 clusters of DNaseI-hypersensitive (DHS) sites with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHS sites and promoters, CpG-islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements, and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHS sites and evaluated the tissue of origin for cancer cell-types. A similar classifier predicted the sex using 3 loci on the X chromosome, including the Xist lincRNA locus. By correlating DHS signal and gene expression, we predicted target genes for >500k DHS sites. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell-types.
- Received November 17, 2012.
- Accepted March 7, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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