Abstract
BackgroundIt is established that protein-coding exons are preferentially localized in nucleosomes. To examine whether the same is true for non-coding exons, we analysed nucleosome occupancy in and adjacent to internal exons in genes encoding long non-coding RNAs (lncRNAs) in human CD4+ T cells and K562 cells.ResultsWe confirmed that internal exons in lncRNAs are preferentially associated with nucleosomes, but also observed an elevated signal from H3K4me3-marked nucleosomes in the sequences upstream of these exons. Examination of 200 genomic lncRNA loci chosen at random across all chromosomes showed that high-density regions of H3K4me3-marked nucleosomes, which we term ‘slabs’, are associated with genomic regions exhibiting intron retention. These retained introns occur in over 50% of lncRNAs examined and are mostly first introns with an average length of just 354 bp, compared to the average length of all human introns of 6355 and 7987 bp in mRNAs and lncRNAs, respectively. Removal of short introns from the dataset abrogated the high upstream H3K4me3 signal, confirming that the association of slabs and short lncRNA introns with intron retention holds genome-wide. The high upstream H3K4me3 signal is also associated with alternatively spliced exons, known to be prominent in lncRNAs. This phenomenon was not observed with mRNAs.ConclusionsThere is widespread intron retention and clustered H3K4me3-marked nucleosomes in short first introns of human long non-coding RNAs, which raises intriguing questions about the relationship of IR to lncRNA function and chromatin organization.
Highlights
The genome is composed of protein-coding and non-coding regions collectively transcribed into a large and complex transcriptome that regulates the cellular machinery
We observed ~ 28% increase in the nucleosome occupancy at long non-coding RNAs (lncRNAs) exons as compared to their flanking introns (Fig. 1A), similar to that observed with exons in protein-coding transcripts (Fig. 1B), indicating that nucleosomes are preferentially and precisely positioned on the long non-coding exons, as they are in as with exons of protein-coding genes
To investigate the role of histone modification on the preferential nucleosome enrichment on lncRNA exons, we analysed the ChIP-Seq data for 12 types of common modifications in the histone modification libraries obtained from CD4+ T cells
Summary
The genome is composed of protein-coding and non-coding regions collectively transcribed into a large and complex transcriptome that regulates the cellular machinery. Hundreds of long non-coding RNAs have been shown to play important roles in cell and developmental biology [21,22,23], as well as in the aetiology of cancer and other diseases [24,25,26,27]. These observations suggest that the regulation of multicellular ontogeny cannot be explained solely by the combinatorial control of gene expression by transcription factors, histone modifiers and other widely expressed proteins, but should include the interaction of regulatory RNAs with them. To examine whether the same is true for non-coding exons, we analysed nucleosome occupancy in and adjacent to internal exons in genes encoding long non-coding RNAs (lncRNAs) in human CD4+ T cells and K562 cells
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