Abstract
It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.
Highlights
It is a widely held view that combinations of post-translational modifications on the N-terminal tails of histones are likely to function as an epigenetic code [1] to regulate aspects of gene expression, including the activity of cis-regulatory elements, and the three phases of transcription
This normalization step would effectively remove any biases in histone modification profiles which could be attributed to differences in nucleosome distribution
Our study provides several lines of evidence pointing to histone modifications as having roles in determining chromatin accessibility, polymerase II (Pol II) movement and co-transcriptional mRNA processing at a global level through exon-intron marking
Summary
It is a widely held view that combinations of post-translational modifications on the N-terminal tails of histones are likely to function as an epigenetic code [1] to regulate aspects of gene expression, including the activity of cis-regulatory elements, and the three phases of transcription (initiation, elongation and termination). In support of this code, systematic studies of histone acetylation and methylation patterns across the human genome have revealed signatures for transcriptionally active and inactive promoters [2,3,4,5,6], distal elements/enhancers [2,4,6], and insulators [2,7]. What is clear is that expressed genes require a dynamic equilibrium between the relaxation and compaction of chromatin [15], and the displacement/replacement of nucleosomes [16,17] as the RNA polymerase II (Pol II) complex moves through the gene during transcription [18]
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