Abstract
BackgroundAlternative splicing (AS) is a post-transcriptional regulatory mechanism for gene expression regulation. Splicing decisions are affected by the combinatorial behavior of different splicing factors that bind to multiple binding sites in exons and introns. These binding sites are called splicing regulatory elements (SREs). Here we develop CoSREM (Combinatorial SRE Miner), a graph mining algorithm to discover combinatorial SREs in human exons. Our model does not assume a fixed length of SREs and incorporates experimental evidence as well to increase accuracy. CoSREM is able to identify sets of SREs and is not limited to SRE pairs as are current approaches.ResultsWe identified 37 SRE sets that include both enhancer and silencer elements. We show that our results intersect with previous results, including some that are experimental. We also show that the SRE set GGGAGG and GAGGAC identified by CoSREM may play a role in exon skipping events in several tumor samples. We applied CoSREM to RNA-Seq data for multiple tissues to identify combinatorial SREs which may be responsible for exon inclusion or exclusion across tissues.ConclusionThe new algorithm can identify different combinations of splicing enhancers and silencers without assuming a predefined size or limiting the algorithm to find only pairs of SREs. Our approach opens new directions to study SREs and the roles that AS may play in diseases and tissue specificity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0698-6) contains supplementary material, which is available to authorized users.
Highlights
Alternative splicing (AS) is a post-transcriptional regulatory mechanism for gene expression regulation
Combinatorial splicing regulatory elements (SREs) discovered in human exons For predicting combinatorial SREs, we chose the highest and the lowest 400 6-mers by LEIsc values to construct the SRE graphs GUESE and GUESS
SRE set (GAGGAC,GGGAGG) and the role it may play in cancer progression We further investigated some of the combinatorial SREs
Summary
Alternative splicing (AS) is a post-transcriptional regulatory mechanism for gene expression regulation. Splicing decisions are affected by the combinatorial behavior of different splicing factors that bind to multiple binding sites in exons and introns. These binding sites are called splicing regulatory elements (SREs). The RNA splicing process depends on recognition, by the spliceosome, of specific sequence elements in premRNAs called core splicing signals. These include the 5’ splice site, the 3’ splice site, and the branch point sequence [8]
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