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Bioinformatics Advance Access originally published online on June 30, 2008
Bioinformatics 2008 24(17):1911-1916; doi:10.1093/bioinformatics/btn335
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Automated mapping of large-scale chromatin structure in ENCODE

Heng Lian 1, William A. Thompson 2, Robert Thurman 3, John A. Stamatoyannopoulos 4,*, William Stafford Noble 4,5,* and Charles E. Lawrence 2,*

1Division of Mathematical Sciences, SPMS, Nanyang Technological University, Singapore, 2Center for Computational Molecular Biology, Division of Applied Mathematics, Brown University, Providence, RI, 3Division of Medical Genetics
4Department of Genome Sciences and 5Department of Computer Science and Engineering, University of Washington, Seattle, WA, USA

*To whom correspondence should be addressed.


  Abstract

Motivation: A recently developed DNaseI assay has given us our first genome-wide view of chromatin structure. In addition to cataloging DNaseI hypersensitive sites, these data allows us to more completely characterize overall features of chromatin accessibility. We employed a Bayesian hierarchical change-point model (CPM), a generalization of a hidden Markov Model (HMM), to characterize tiled microarray DNaseI sensitivity data available from the ENCODE project.

Results: Our analysis shows that the accessibility of chromatin to cleavage by DNaseI is well described by a four state model of local segments with each state described by a continuous mixture of Gaussian variables. The CPM produces a better fit to the observed data than the HMM. The large posterior probability for the four-state CPM suggests that the data falls naturally into four classes of regions, which we call major and minor DNaseI hypersensitive sites (DHSs), regions of intermediate sensitivity, and insensitive regions. These classes agree well with a model of chromatin in which local disruptions (DHSs) are concentrated within larger domains of intermediate sensitivity, the accessibility islands. The CPM assigns 92% of the bases within the ENCODE regions to the insensitive regions. The 5.8% of the bases that are in regions of intermediate sensitivity are clearly enriched in functional elements, including genes and activating histone modifications, while the remaining 2.2% of the bases in hypersensitive regions are very strongly enriched in these elements.

Availability: The CPM software is available upon request from the authors.

Contact: jstam{at}stamlab.org; noble{at}gs.washington.edu; Charles_Lawrence{at}brown.edu

Supplementary information: Supplementary data are available at Bioinformatics online. Source code is available at http://noble.gs.washington.edu/proj/segment.

Associate Editor: Jonathan Wren

Received on May 15, 2008; revised on June 28, 2008; accepted on June 28, 2008

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