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Bioinformatics. 2019 Mar 15;35(6):903-913. doi: 10.1093/bioinformatics/bty703.

Characterizing protein-DNA binding event subtypes in ChIP-exo data.

Author information

1
Department of Biochemistry & Molecular Biology and Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA, USA.

Abstract

MOTIVATION:

Regulatory proteins associate with the genome either by directly binding cognate DNA motifs or via protein-protein interactions with other regulators. Each recruitment mechanism may be associated with distinct motifs and may also result in distinct characteristic patterns in high-resolution protein-DNA binding assays. For example, the ChIP-exo protocol precisely characterizes protein-DNA crosslinking patterns by combining chromatin immunoprecipitation (ChIP) with 5' → 3' exonuclease digestion. Since different regulatory complexes will result in different protein-DNA crosslinking signatures, analysis of ChIP-exo tag enrichment patterns should enable detection of multiple protein-DNA binding modes for a given regulatory protein. However, current ChIP-exo analysis methods either treat all binding events as being of a uniform type or rely on motifs to cluster binding events into subtypes.

RESULTS:

To systematically detect multiple protein-DNA interaction modes in a single ChIP-exo experiment, we introduce the ChIP-exo mixture model (ChExMix). ChExMix probabilistically models the genomic locations and subtype memberships of binding events using both ChIP-exo tag distribution patterns and DNA motifs. We demonstrate that ChExMix achieves accurate detection and classification of binding event subtypes using in silico mixed ChIP-exo data. We further demonstrate the unique analysis abilities of ChExMix using a collection of ChIP-exo experiments that profile the binding of key transcription factors in MCF-7 cells. In these data, ChExMix identifies possible recruitment mechanisms of FoxA1 and ERα, thus demonstrating that ChExMix can effectively stratify ChIP-exo binding events into biologically meaningful subtypes.

AVAILABILITY AND IMPLEMENTATION:

ChExMix is available from https://github.com/seqcode/chexmix.

SUPPLEMENTARY INFORMATION:

Supplementary data are available at Bioinformatics online.

PMID:
30165373
PMCID:
PMC6419906
[Available on 2020-03-15]
DOI:
10.1093/bioinformatics/bty703
[Indexed for MEDLINE]

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