Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape

• Main Authors: Lewis, Sophia (Author), van Hoff, John Peter (Author), Karun, Vivek (Author), Hashimoto, Tatsunori Benjamin (Contributor), Sherwood, Richard I. (Author), O'Donnell, Charles William (Contributor), Barkal, Amira A. (Author), Jaakkola, Tommi S. (Contributor), Gifford, David K. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory (Contributor), Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2015-12-14T02:21:40Z.
• Subjects: Article
• Online Access: Get fulltext

We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase I hypersensitivity analysis followed by sequencing (DNase-seq) experiment with accuracy comparable to that of chromatin immunoprecipitation followed by sequencing (ChIP-seq). We applied PIQ to analyze DNase-seq data from mouse embryonic stem cells differentiating into prepancreatic and intestinal endoderm. We identified 120 and experimentally validated eight 'pioneer' TF families that dynamically open chromatin. Four pioneer TF families only opened chromatin in one direction from their motifs. Furthermore, we identified 'settler' TFs whose genomic binding is principally governed by proximity to open chromatin. Our results support a model of hierarchical TF binding in which directional and nondirectional pioneer activity shapes the chromatin landscape for population by settler TFs.
National Institutes of Health (U.S.) (Common Fund 5UL1DE019581)
National Institutes of Health (U.S.) (Common Fund RL1DE019021)
National Institutes of Health (U.S.) (Common Fund 5TL1EB008540)
National Institutes of Health (U.S.) (Grant 1U01HG007037)
National Institutes of Health (U.S.) (Grant 5P01NS055923)