Regulation of alternative splicing: Functional interplay with epigenetic modifications and its implication to cancer

Eukaryotic gene expression is intricately regulated at multiple levels. The protein-coding genes are first transcribed as pre-mRNAs in the nucleus and undergo a series of RNA processing steps before being transported into the cytoplasm for translation. During RNA processing, most human genes (>95%) undergo alternative splicing to generate multiple mRNA isoforms from a single gene, which effectively diversifies the genome complexity. Since the splicing of most genes occurs co-transcriptionally, the regulation layers of gene expression often show functional interactions with each other. In this review, we provide a brief overview of alternative splicing regulation in three different layers (controlled by the splicing machinery, transcription process, and chromatin structure), emphasizing the regulatory roles of epigenetic modifications and the crosstalk between these layers. Specifically, we categorize the major effects of the epigenetic modifications on alternative splicing into three different types: by affecting transcription rate, splicing factor recruitment, or the expression/activity of splicing factor. The dysregulation of epigenetics and splicing are extremely common in cancer, we also discuss the potential mechanisms of how epigenetic changes can lead to splicing dysregulation and their functional consequences. We aim to provide insights into the complicated regulation of different gene expression layers, which will shed light on the novel approaches to modulate disease-related splicing dysregulation. This article is categorized under: RNA Processing > 30 End Processing RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease