Predicting cell-type–specific gene expression from regions of open chromatin
- Anirudh Natarajan1,
- Galip Gürkan Yardımcı1,
- Nathan C. Sheffield1,
- Gregory E. Crawford2,3,5 and
- Uwe Ohler2,4,5
- 1Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina 27708, USA;
- 2Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina 27708, USA;
- 3Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina 27708, USA;
- 4Department of Biostatistics & Bioinformatics, Duke University, Durham, North Carolina 27708, USA
Abstract
Complex patterns of cell-type–specific gene expression are thought to be achieved by combinatorial binding of transcription factors (TFs) to sequence elements in regulatory regions. Predicting cell-type–specific expression in mammals has been hindered by the oftentimes unknown location of distal regulatory regions. To alleviate this bottleneck, we used DNase-seq data from 19 diverse human cell types to identify proximal and distal regulatory elements at genome-wide scale. Matched expression data allowed us to separate genes into classes of cell-type–specific up-regulated, down-regulated, and constitutively expressed genes. CG dinucleotide content and DNA accessibility in the promoters of these three classes of genes displayed substantial differences, highlighting the importance of including these aspects in modeling gene expression. We associated DNase I hypersensitive sites (DHSs) with genes, and trained classifiers for different expression patterns. TF sequence motif matches in DHSs provided a strong performance improvement in predicting gene expression over the typical baseline approach of using proximal promoter sequences. In particular, we achieved competitive performance when discriminating up-regulated genes from different cell types or genes up- and down-regulated under the same conditions. We identified previously known and new candidate cell-type–specific regulators. The models generated testable predictions of activating or repressive functions of regulators. DNase I footprints for these regulators were indicative of their direct binding to DNA. In summary, we successfully used information of open chromatin obtained by a single assay, DNase-seq, to address the problem of predicting cell-type–specific gene expression in mammalian organisms directly from regulatory sequence.
Footnotes
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↵5 Corresponding authors
E-mail greg.crawford{at}duke.edu
E-mail uwe.ohler{at}duke.edu
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[Supplemental material is available for this article.]
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Article and supplemental material are at http://www.genome.org/cgi/doi/10.1101/gr.135129.111.
Freely available online through the Genome Research Open Access option.
- Received November 21, 2011.
- Accepted June 8, 2012.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
