Abstract
Mechanisms that generate transcript diversity are of fundamental importance in eukaryotes. Although a large fraction of human protein-coding genes and lincRNAs produce more than one mRNA isoform each, the regulation of this phenomenon is still incompletely understood. Much progress has been made in deciphering the role of sequence-specific features as well as DNA-and RNA-binding proteins in alternative splicing. Recently, however, several experimental studies of individual genes have revealed a direct involvement of epigenetic factors in alternative splicing and transcription initiation. While histone modifications are generally correlated with overall gene expression levels, it remains unclear how histone modification enrichment affects relative isoform abundance. Therefore, we sought to investigate the associations between histone modifications and transcript diversity levels measured by the rates of transcription start-site switching and alternative splicing on a genome-wide scale across protein-coding genes and lincRNAs. We found that the relationship between enrichment levels of epigenetic marks and transcription start-site switching is similar for protein-coding genes and lincRNAs. Furthermore, we found associations between splicing rates and enrichment levels of H2az, H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K27ac, H3K27me3, H3K36me3, H3K79me2, and H4K20me, marks traditionally associated with enhancers, transcription initiation, transcriptional repression, and others. These patterns were observed in both normal and cancer cell lines. Additionally, we developed a novel computational method that identified 840 epigenetically regulated candidate genes and predicted transcription start-site switching and alternative exon splicing with up to 92% accuracy based on epigenetic patterning alone. Our results suggest that the epigenetic regulation of transcript isoform diversity may be a relatively common genome-wide phenomenon representing an avenue of deregulation in tumor development.
Highlights
Molecular processes such as alternative splicing and transcription start-site switching are primary drivers of transcript diversity
We developed a computational approach to investigate the genome-wide prevalence and the level of association between the enrichment of epigenetic marks and transcript diversity generated via alternative transcription start sites and splicing
We found that the role of epigenetic patterning in alternative transcription start-site switching is likely to be the same for all genes whereas the role of epigenetic patterns in splicing is likely gene-specific
Summary
Molecular processes such as alternative splicing and transcription start-site switching are primary drivers of transcript diversity. Experimental studies have expanded to include other regulatory factors such as histone modifications, suggesting that epigenetic features may have the ability to determine when and in which tissues certain genes are expressed, and to influence how these transcripts are processed. Genome-wide analyses indicate that nucleosomes and histone modifications are not randomly distributed, but often coincide with exon boundaries [5,6,7]. This observation, combined with recent evidence that most events of alternative splicing in human cells occur co-transcriptionally [8,9], strongly suggest a regulatory potential of histone marks [2,10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
