Abstract
BackgroundCombinations of histone variants and modifications, conceptually representing a histone code, have been proposed to play a significant role in gene regulation and developmental processes in complex organisms. While various mechanisms have been implicated in establishing and maintaining epigenetic patterns at specific locations in the genome, they are generally believed to be independent of primary DNA sequence on a more global scale.ResultsTo address this systematically in the case of the human genome, we have analyzed primary DNA sequences underlying patterns of 19 different methylated histones in human primary T-cells and patterns of three methylated histones across additional human cell lines. We report strong sequence biases associated with most of these histone marks genome-wide in each cell type. Furthermore, the sequence characteristics for such association are distinct for different groups of histone marks.ConclusionsThese findings provide evidence of an influence of genomic sequence on patterns of histone modification associated with gene expression and chromatin programming, and they suggest that the mechanisms responsible for global histone modifications may interpret genomic sequence in various ways.
Highlights
Combinations of histone variants and modifications, conceptually representing a histone code, have been proposed to play a significant role in gene regulation and developmental processes in complex organisms
The histone code or epigenetic code theory proposes that the combinatorial nature of histone modifications and histone variants represents information that greatly extends the content and display of genetic information alone [3,4,5,6,7,8]
Genomic sequence alone discriminates regions enriched or depleted for most methylated histones in human CD4+ cells To investigate whether histone marks in general are associated with underlying genomic sequence, we analyzed a dataset containing the profiles of different methylated histones from genome-wide ChIP followed by deep sequencing experiments (ChIP-Seq) in human CD4+ T-cells [29]. (Of the marks reported by Barski et al [29], H3K29me2 was excluded because of low sequence coverage in the original dataset.) We asked whether genomic sequence could distinguish between regions that are enriched or depleted for these histone marks in this cell type
Summary
Combinations of histone variants and modifications, conceptually representing a histone code, have been proposed to play a significant role in gene regulation and developmental processes in complex organisms. While various mechanisms have been implicated in establishing and maintaining epigenetic patterns at specific locations in the genome, they are generally believed to be independent of primary DNA sequence on a more global scale. Nucleosomes can adopt distinct chromatin structures, associated with specific posttranslational modifications of histone proteins at their N-terminal tails [2]. Such histone modifications can be stably maintained through cell divisions and are strong candidates to serve as marks for epigenetic regulation. Epigenetic modifications either influence the accessibility of cis-regulatory elements in genomic DNA or recruit chromatin-binding proteins to regulate gene expression. As one approach to testing this model, a number of studies have begun to define genome-scale maps of various histone modifications and other chromatin constituents and to
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