Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors

Zhenqing Ye, Zhong Chen, Xun Lan, Stephen Hara, Benjamin Sunkel, Hui-ming Huang, Laura Elnitski, Qianben Wang, Victor X Jin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Alternative splicing (AS), in higher eukaryotes, is one of the mechanisms of post-transcriptional regulation that generate multiple transcripts from the same gene. One particular mode of AS is the skipping event where an exon may be alternatively excluded or constitutively included in the resulting mature mRNA. Both transcript isoforms from this skipping event site, i.e. in which the exon is either included (inclusion isoform) or excluded (skipping isoform), are typically present in one cell, and maintain a subtle balance that is vital to cellular function and dynamics. However, how the prevailing conditions dictate which isoform is expressed and what biological factors might influence the regulation of this process remain areas requiring further exploration. In this study, we have developed a novel computational method, graph-based exon-skipping scanner (GESS), for de novo detection of skipping event sites from raw RNA-seq reads without prior knowledge of gene annotations, as well as for determining the dominant isoform generated from such sites. We have applied our method to publicly available RNA-seq data in GM12878 and K562 cells from the ENCODE consortium and experimentally validated several skipping site predictions by RT-PCR. Furthermore, we integrated other sequencing-based genomic data to investigate the impact of splicing activities, transcription factors (TFs) and epigenetic histone modifications on splicing outcomes. Our computational analysis found that splice sites within the skipping-isoform-dominated group (SIDG) tended to exhibit weaker MaxEntScan-calculated splice site strength around middle, 'skipping', exons compared to those in the inclusion-isoform- dominated group (IIDG). We further showed the positional preference pattern of splicing factors, characterized by enrichment in the intronic splice sites immediately bordering middle exons. Finally, our analysis suggested that different epigenetic factors may introduce a variable obstacle in the process of exon-intron boundary establishment leading to skipping events.

Original languageEnglish (US)
Pages (from-to)2856-2869
Number of pages14
JournalNucleic Acids Research
Volume42
Issue number5
DOIs
StatePublished - 2014

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Epigenomics
Exons
Protein Isoforms
Transcription Factors
Alternative Splicing
Histone Code
RNA
Molecular Sequence Annotation
K562 Cells
Biological Factors
Eukaryota
Introns
Polymerase Chain Reaction
Messenger RNA
Genes

ASJC Scopus subject areas

  • Genetics

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Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors. / Ye, Zhenqing; Chen, Zhong; Lan, Xun; Hara, Stephen; Sunkel, Benjamin; Huang, Hui-ming; Elnitski, Laura; Wang, Qianben; Jin, Victor X.

In: Nucleic Acids Research, Vol. 42, No. 5, 2014, p. 2856-2869.

Research output: Contribution to journalArticle

Ye, Zhenqing ; Chen, Zhong ; Lan, Xun ; Hara, Stephen ; Sunkel, Benjamin ; Huang, Hui-ming ; Elnitski, Laura ; Wang, Qianben ; Jin, Victor X. / Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 5. pp. 2856-2869.
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