Interplay between chromatin state, regulator binding, and regulatory motifs in six human cell types
- Jason Ernst1,2,3,4 and
- Manolis Kellis5,6,7
- 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles,
- 2Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA,
- 3Jonsson Comprehensive Cancer Center, University of California, Los Angeles,
- 4Molecular Biology Institute, University of California, Los Angeles, California 90095, USA;
- 5MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA;
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Abstract
The regions bound by sequence-specific transcription factors can be highly variable across different cell types despite the static nature of the underlying genome sequence. This has been partly attributed to changes in chromatin accessibility, but a systematic picture has been hindered by the lack of large-scale data sets. Here, we use 456 binding experiments for 119 regulators and 84 chromatin maps generated by the ENCODE in six human cell types, and relate those to a global map of regulatory motif instances for these factors. We find specific and robust chromatin state preferences for each regulator beyond the previously reported open-chromatin association, suggesting a much richer chromatin landscape beyond simple accessibility. The preferentially bound chromatin states of regulators were enriched for sequence motifs of regulators relative to all states, suggesting that these preferences are at least partly encoded by the genomic sequence. Relative to all regions bound by a regulator, however, regulatory motifs were surprisingly depleted in the regulator's preferentially bound states, suggesting additional non-sequence-specific binding beyond the level predicted by the regulatory motifs. Such permissive binding was largely restricted to open-chromatin regions showing histone modification marks characteristic of active enhancer and promoter regions, whereas open-chromatin regions lacking such marks did not show permissive binding. Lastly, the vast majority of cobinding of regulator pairs is predicted by the chromatin state preferences of individual regulators. Overall, our results suggest a joint role of sequence motifs and specific chromatin states beyond mere accessibility in mediating regulator binding dynamics across different cell types.
Footnotes
-
↵7 Corresponding author
E-mail manoli{at}mit.edu
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.144840.112.
Freely available online through the Genome Research Open Access option.
- Received June 29, 2012.
- Accepted April 2, 2013.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
