Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

Jin Li,Hong Liang,Yang Wang,Xianglian Meng

doi:10.7717/peerj.4686

Abstract

Proteins that modify the activity of transcription factors (TFs) are often called modulators and play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing, and differentially spliced isoforms may have different functions. Alternative splicing can modulate gene function by adding or removing certain protein domains and thereby influence the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various disorders, including Alzheimer’s disease and Down syndrome. The results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. In addition, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. The results of our analysis suggest that alternatively spliced proteins have different functions in modifying transcription factors and can thereby induce the dysregulation of multiple genes.

Highlights

Alternative splicing (AS) is a key regulator of gene expression as it generates numerous transcripts from a single protein-coding gene
EST domain-containing protein Elk-1 (ELK1) was one of the 26 transcription factors (TFs) that had the greatest number of predicted modulators
A total of 262 splicing events corresponding to 187 proteins were identified as ELK1 modulators because their splicing outcomes highly correlated with changes in the transcriptional activity of ELK1

Summary

Introduction

Alternative splicing (AS) is a key regulator of gene expression as it generates numerous transcripts from a single protein-coding gene. More than 95% of multi-exonic protein-coding genes undergo AS (Wang et al, 2008), and AS plays an important role in cellular differentiation and organism development (Castle et al, 2008; Wang et al, 2008). As AS affects numerous genes and is highly important for regulating the normal expression and tissue specificity of a given gene, it is not surprising that changes in AS are frequently associated with human disease, such as cancers (Kozlovski et al, 2017) and neurodegenerative diseases (Scotti & Swanson, 2016). Widespread splicing changes, such as altered cassette exon inclusion ratios of proteins, influence the expression of numerous genes and cause aberrant gene regulation.

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