Abstract
Transcription factor (TF) binding at specific DNA sequences is the fundamental step in transcriptional regulation and is highly dependent on the chromatin structure context, which may be affected by specific histone modifications and variants, known as histone marks. The lack of a global binding map for hundreds of TFs means that previous studies have focused mainly on histone marks at binding sites for several specific TFs. We therefore studied 11 histone marks around computationally-inferred and experimentally-determined TF binding sites (TFBSs), based on 164 and 34 TFs, respectively, in human lymphoblastoid cell lines. For H2A.Z, methylation of H3K4, and acetylation of H3K27 and H3K9, the mark patterns exhibited bimodal distributions and strong pairwise correlations in the 600-bp region around enriched TFBSs, suggesting that these marks mainly coexist within the two nucleosomes proximal to the TF sites. TFs competing with nucleosomes to access DNA at most binding sites, contributes to the bimodal distribution, which is a common feature of histone marks for TF binding. Mark H3K79me2 showed a unimodal distribution on one side of TFBSs and the signals extended up to 4000 bp, indicating a longer-distance pattern. Interestingly, H4K20me1, H3K27me3, H3K36me3 and H3K9me3, which were more diffuse and less enriched surrounding TFBSs, showed unimodal distributions around the enriched TFBSs, suggesting that some TFs may bind to nucleosomal DNA. Besides, asymmetrical distributions of H3K36me3 and H3K9me3 indicated that repressors might establish a repressive chromatin structure in one direction to repress gene expression. In conclusion, this study demonstrated the ranges of histone marks associated with TF binding, and the common features of these marks around the binding sites. These findings have epigenetic implications for future analysis of regulatory elements.
Highlights
Most eukaryotic genomic DNA is packaged into chromatin structure to achieve high compaction
Previous studies found that some enhancers were marked by histone modification H3K4me1 or H3K4me2 [15,16], while our results indicated higher frequencies of H2A.Z, H3K4me3, H3K27ac and H3K9ac at Transcription factors (TFs) binding sites (TFBSs)
All the histone marks were more enriched at CENTIPEDE sites compared with the genome as a whole (One-sided binomial test, p,2.2610216), indicating an association between histone modifications and TF binding in transcription
Summary
Most eukaryotic genomic DNA is packaged into chromatin structure to achieve high compaction. Nucleosomal histones are subject to specific posttranslational modifications and variants, known as histone marks, which may affect the chromatin structure and play crucial roles in regulating gene expression in a cell-typespecific manner [3,4,5,6,7]. A comprehensive analysis of 39 different histone methylation and acetylation marks in human CD4+T cells has indicated that most modifications, except H3K27me, H3K27me, H3K9me, H3K9me and H4K20me, are associated with gene activation [8,9], and specific combinations of chromatin marks are correlated with various genomic regions [5,10]. Transcription factors (TFs) bind to specific DNA sequences and interact with components of the polymerase complex or with other complexes to initiate transcription in eukaryotes, and this process is highly associated with specific histone variants and modifications [11,12,13,14]. Previous studies have focused mainly on histone marks around binding sites for few specific TFs
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