title: Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution.
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.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Pawandeep
authors.initials: P
authors.lastname: Dhami
authors.forename: Peter
authors.initials: P
authors.lastname: Saffrey
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Bruce
authors.forename: Shane C
authors.initials: SC
authors.lastname: Dillon
authors.forename: Kelly
authors.initials: K
authors.lastname: Chiang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonhoure
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Koch
authors.forename: Jackie
authors.initials: J
authors.lastname: Bye
authors.forename: Keith
authors.initials: K
authors.lastname: James
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Foad
authors.forename: Peter
authors.initials: P
authors.lastname: Ellis
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Watkins
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Cordelia
authors.initials: C
authors.lastname: Langford
authors.forename: Robert M
authors.initials: RM
authors.lastname: Andrews
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.forename: David
authors.initials: D
authors.lastname: Vetrie
mesh_terms: D005091:Exons / Q000235:genetics*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics*; D020014:K562 Cells; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D009707:Nucleosomes; D012319:RNA Polymerase II
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