A global genome segmentation method for exploration of epigenetic patterns

PLoS One. 2012;7(10):e46811. doi: 10.1371/journal.pone.0046811. Epub 2012 Oct 12.

Abstract

Current genome-wide ChIP-seq experiments on different epigenetic marks aim at unraveling the interplay between their regulation mechanisms. Published evaluation tools, however, allow testing for predefined hypotheses only. Here, we present a novel method for annotation-independent exploration of epigenetic data and their inter-correlation with other genome-wide features. Our method is based on a combinatorial genome segmentation solely using information on combinations of epigenetic marks. It does not require prior knowledge about the data (e.g. gene positions), but allows integrating the data in a straightforward manner. Thereby, it combines compression, clustering and visualization of the data in a single tool. Our method provides intuitive maps of epigenetic patterns across multiple levels of organization, e.g. of the co-occurrence of different epigenetic marks in different cell types. Thus, it facilitates the formulation of new hypotheses on the principles of epigenetic regulation. We apply our method to histone modification data on trimethylation of histone H3 at lysine 4, 9 and 27 in multi-potent and lineage-primed mouse cells, analyzing their combinatorial modification pattern as well as differentiation-related changes of single modifications. We demonstrate that our method is capable of reproducing recent findings of gene centered approaches, e.g. correlations between CpG-density and the analyzed histone modifications. Moreover, combining the clustered epigenetic data with information on the expression status of associated genes we classify differences in epigenetic status of e.g. house-keeping genes versus differentiation-related genes. Visualizing the distribution of modification states on the chromosomes, we discover strong patterns for chromosome X. For example, exclusively H3K9me3 marked segments are enriched, while poised and active states are rare. Hence, our method also provides new insights into chromosome-specific epigenetic patterns, opening up new questions how "epigenetic computation" is distributed over the genome in space and time.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Cell Differentiation
  • Cell Lineage
  • DNA Methylation
  • Epigenesis, Genetic*
  • Epigenomics / methods*
  • Genes, Essential
  • Genome
  • Histones / genetics*
  • Mice

Substances

  • Histones

Grants and funding

LS and TR are supported by the BMBF grant MAGE (grant number 50500541). LH and HW are funded by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes, and Environment (LIFE Center, University of Leipzig). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), the European Social Fund (ESF), and by means of the Free State of Saxony within the framework of its excellence initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.