Combinatorial binding of transcription factors in the pluripotency control regions of the genome
- Luciana Ferraris1,4,
- Allan P. Stewart2,4,
- Jinsuk Kang3,4,
- Alec M. DeSimone1,
- Matthew Gemberling1,
- Dean Tantin3 and
- William G. Fairbrother1,2,5
- 1Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA;
- 2Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA;
- 3Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
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↵4 These authors contributed equally to this work.
Abstract
The pluripotency control regions (PluCRs) are defined as genomic regions that are bound by POU5F1, SOX2, and NANOG in vivo. We utilized a high-throughput binding assay to record more than 270,000 different DNA/protein binding measurements along incrementally tiled windows of DNA within these PluCRs. This high-resolution binding map is then used to systematically define the context of POU factor binding, and reveals patterns of cooperativity and competition in the pluripotency network. The most prominent pattern is a pervasive binding competition between POU5F1 and the forkhead transcription factors. Like many transcription factors, POU5F1 is co-expressed with a paralog, POU2F1, that shares an apparently identical binding specificity. By analyzing thousands of binding measurements, we discover context effects that discriminate POU2F1 from POU5F1 binding. Proximal NANOG binding promotes POU5F1 binding, whereas nearby SOX2 binding favors POU2F1. We demonstrate by cross-species comparison and by chromatin immunoprecipitation (ChIP) that the contextual sequence determinants learned in vitro are sufficient to predict POU2F1 binding in vivo.
Footnotes
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↵5 Corresponding author.
E-mail fairbrother{at}brown.edu.
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[Supplemental material is available for this article. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE27535.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.115824.110.
- Received September 24, 2010.
- Accepted March 8, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
