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

• Published in: Nature biotechnology Vol. 32; no. 2; pp. 171 - 178
• Main Authors: Sherwood, Richard I, Hashimoto, Tatsunori, O'Donnell, Charles W, Lewis, Sophia, Barkal, Amira A, van Hoff, John Peter, Karun, Vivek, Jaakkola, Tommi, Gifford, David K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2014; Nature Publishing Group
• Subjects: 13/31; 13/44; 45/100; 45/23; 631/114/1305; 631/114/2785; 631/532/2117; 631/553/2711; Agriculture; analysis; Binding sites; Binding Sites - genetics; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Chromatin; Computational Biology - methods; Deoxyribonucleases - chemistry; Deoxyribonucleases - genetics; Deoxyribonucleases - metabolism; Deoxyribonucleic acid; DNA; Enzymes; Genomics; Hypersensitivity; Life Sciences; Models, Genetic; Physiological aspects; Protein Binding; Protein research; Protein-protein interactions; Proteins; Stem cells; Transcription factors; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; United States
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.2798

A new algorithm learns features of chromatin profiles left by transcription factors, shedding light on when DNA sequence motifs are bound. 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.