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Joint annotation of chromatin state and chromatin conformation reveals relationships among domain types and identifies domains of cell type-specific expression

Maxwell W. Libbrecht, Ferhat Ay, Michael M. Hoffman, David M. Gilbert, Jeffrey A. Bilmes, William Stafford Noble
doi: https://doi.org/10.1101/009209
Maxwell W. Libbrecht
1Department of Computer Science and Engineering, University of Washington
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Ferhat Ay
2Department of Genome Sciences, University of Washington
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Michael M. Hoffman
3Princess Margaret Cancer Centre
4Department of Medical Biophysics, University of Toronto
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David M. Gilbert
5Department of Biological Science, Florida State University
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Jeffrey A. Bilmes
6Department of Electrical Engineering, University of Washington
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William Stafford Noble
2Department of Genome Sciences, University of Washington
1Department of Computer Science and Engineering, University of Washington
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Abstract

The genomic neighborhood of a gene influences its activity, a behavior that is attributable in part to domain-scale regulation, in which regions of hundreds or thousands of kilobases known as domains are regulated as a unit. Previous studies using genomics assays such as chromatin immunoprecipitation (ChIP)-seq and chromatin conformation capture (3C)-based assays have identified many types of regulatory domains. However, due to the difficulty of integrating genomics data sets, the relationships among these domain types are poorly understood. Semi-automated genome annotation (SAGA) algorithms facilitate human interpretation of heterogeneous collections of genomics data by simultaneously partitioning the human genome and assigning labels to the resulting genomic segments. However, existing SAGA methods can incorporate only data sets that can be expressed as a one-dimensional vector over the genome and therefore cannot integrate inherently pairwise chromatin conformation data. We developed a new computational method, called graph-based regularization (GBR), for expressing a pairwise prior that encourages certain pairs of genomic loci to receive the same label in a genome annotation. We used GBR to exploit chromatin conformation information during genome annotation by encouraging positions that are close in 3D to occupy the same type of domain. Using this approach, we produced a comprehensive model of chromatin domains in eight human cell types, thereby revealing the relationships among known domain types. Through this model, we identified clusters of tightly-regulated genes expressed in only a small number of cell types, which we term “specific expression domains.” We additionally found that a subset of domain boundaries marked by promoters and CTCF motifs are consistent between cell types even when domain activity changes. Finally, we showed that GBR can be used for the seemingly unrelated task of transferring information from well-studied cell types to less well characterized cell types during genome annotation, making it possible to produce high-quality annotations of the hundreds of cell types with limited available data.

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Posted September 16, 2014.
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Joint annotation of chromatin state and chromatin conformation reveals relationships among domain types and identifies domains of cell type-specific expression
Maxwell W. Libbrecht, Ferhat Ay, Michael M. Hoffman, David M. Gilbert, Jeffrey A. Bilmes, William Stafford Noble
bioRxiv 009209; doi: https://doi.org/10.1101/009209
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Joint annotation of chromatin state and chromatin conformation reveals relationships among domain types and identifies domains of cell type-specific expression
Maxwell W. Libbrecht, Ferhat Ay, Michael M. Hoffman, David M. Gilbert, Jeffrey A. Bilmes, William Stafford Noble
bioRxiv 009209; doi: https://doi.org/10.1101/009209

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