Bioinformatics challenges and perspectives when studying the effect of epigenetic modifications on alternative splicing

Abstract

It is widely known that epigenetic modifications are important in regulating transcription, but several have also been reported in alternative splicing. The regulation of pre-mRNA splicing is important to explain proteomic diversity and the misregulation of splicing has been implicated in many diseases. Here, we give a brief overview of the role of epigenetics in alternative splicing and disease. We then discuss the bioinformatics methods that can be used to model interactions between epigenetic marks and regulators of splicing. These models can be used to identify alternative splicing and epigenetic changes across different phenotypes.This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution

“…As the number of new ''omics'' technologies continues to grow, generating new types of transcriptomic datasets with which to derive the principles of gene regulation, it is becoming increasingly apparent that underexplored alternative splicing mechanisms await further investigation. For example, an increasing arsenal of omics methods is being used to map different types of RNA modifications comprising the ''epitranscriptome,'' and an important area for future study will be to determine how these may affect alternative splicing as well as other steps in post-transcriptional gene regulation (Haussmann et al, 2016;Lence et al, 2016;Pacini and Koziol, 2018;Shi et al, 2019;Zhou et al, 2019). Similarly, methods for transcriptome-wide mapping of spliceosomal assembly and RNA-RNA contacts, including both intra-and inter-molecular contacts, will be important for understanding how RNA structures regulate the formation of functional RNP complexes and the availability of splice sites or the contacts between splice sites, which can facilitate either regular splicing or back-splicing during circular RNA (circRNA) biogenesis (Aw et al, 2016;Briese et al, 2019;Burke et al, 2018;Chen et al, 2018;Kristensen et al, 2019;Lu et al, 2016;Nguyen et al, 2016;Sharma et al, 2016).…”

Chromatin accessibility determines intron retention in a cell type-specific manner

“…Moreover, some models were developed to predict cryptic splicing events caused by genetic variations and to link these to human diseases (Baeza-Centurion et al, 2019; Jaganathan et al, 2019; Xiong et al, 2015). However, the computational prediction of IR events has not been attempted to date and the role of epigenetic marks has rarely been considered in computational models of splicing regulation (Monteuuis et al, 2019; Pacini and Koziol, 2018).…”

Aberrant RNA splicing due to genetic incompatibilities in sunflower hybrids

“…We want to draw attention to aberrant RNA splicing as a possible mechanistic basis for hybrid inviability caused by DM, and other types of, hybrid incompatibilities. It is intuitive that incompatibilities might affect splicing, because alternative splicing ordinarily relies on epistatic gene networks (Munding et al 2010;Julien et al 2016;Pacini et al 2018) involving hundreds of regulatory loci for the assembly and regulation of the spliceosome (Will and Lührmann. 2011).…”

“…The removal of introns and joining of exons is accomplished via the spliceosome-a complex consisting of hundreds of protein and RNA components (Will and Lührmann 2011)-and additional regulatory factors, for example, serine/arginine-rich (SR) proteins. Genetic regulation of splicing is highly complex, partly due to the sheer number of genes involved, but also due to its intricate epistatic networks (Munding et al 2010;Julien et al 2016;Pacini and Koziol 2018). It was previously thought that these regulatory networks were tightly conserved (Sorek and Ast.…”