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Open Access Highly Accessed Methodology article

MMDiff: quantitative testing for shape changes in ChIP-Seq data sets

Gabriele Schweikert12*, Botond Cseke1, Thomas Clouaire23, Adrian Bird2 and Guido Sanguinetti1*

Author Affiliations

1 School of Informatics, University of Edinburgh, 10 Crichton Street, Edinburgh EH89AB, UK

2 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK

3 Present address: LBCMCP, Université Paul Sabatier- CNRS UMR 5088, 118 Route de Narbonne, 31062 Toulouse cedex, France

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BMC Genomics 2013, 14:826  doi:10.1186/1471-2164-14-826

Published: 24 November 2013

Abstract

Background

Cell-specific gene expression is controlled by epigenetic modifications and transcription factor binding. While genome-wide maps for these protein-DNA interactions have become widely available, quantitative comparison of the resulting ChIP-Seq data sets remains challenging. Current approaches to detect differentially bound or modified regions are mainly borrowed from RNA-Seq data analysis, thus focusing on total counts of fragments mapped to a region, ignoring any information encoded in the shape of the peaks.

Results

Here, we present MMDiff, a robust, broadly applicable method for detecting differences between sequence count data sets. Based on quantifying shape changes in signal profiles, it overcomes challenges imposed by the highly structured nature of the data and the paucity of replicates.

We first use a simulated data set to compare the performance of MMDiff with results obtained by four alternative methods. We demonstrate that MMDiff excels when peak profiles change between samples. We next use MMDiff to re-analyse a recent data set of the histone modification H3K4me3 elucidating the establishment of this prominent epigenomic marker. Our empirical analysis shows that the method yields reproducible results across experiments, and is able to detect functional important changes in histone modifications. To further explore the broader applicability of MMDiff, we apply it to two ENCODE data sets: one investigating the histone modification H3K27ac and one measuring the genome-wide binding of the transcription factor CTCF. In both cases, MMDiff proves to be complementary to count-based methods. In addition, we can show that MMDiff is capable of directly detecting changes of homotypic binding events at neighbouring binding sites. MMDiff is readily available as a Bioconductor package.

Conclusions

Our results demonstrate that higher order features of ChIP-Seq peaks carry relevant and often complementary information to total counts, and hence are important in assessing differential histone modifications and transcription factor binding. We have developed a new computational method, MMDiff, that is capable of exploring these features and therefore closes an existing gap in the analysis of ChIP-Seq data sets.

Keywords:
Chip-Seq; Differential peak detection; Kernel methods; Maximum mean discrepancy; Histone modifications; H3K4me3; Cfp1