Connecting the dots: chromatin and alternative splicing in EMT

Abstract

Nature has devised sophisticated cellular machinery to process mRNA transcripts produced by RNA Polymerase II, removing intronic regions and connecting exons together, to produce mature RNAs. This process, known as splicing, is very closely linked to transcription. Alternative splicing, or the ability to produce different combinations of exons that are spliced together from the same genomic template, is a fundamental means of regulating protein complexity. Similar to transcription, both constitutive and alternative splicing can be regulated by chromatin and its associated factors in response to various signal transduction pathways activated by external stimuli. This regulation can vary between different cell types, and interference with these pathways can lead to changes in splicing, often resulting in aberrant cellular states and disease. The epithelial to mesenchymal transition (EMT), which leads to cancer metastasis, is influenced by alternative splicing events of chromatin remodelers and epigenetic factors such as DNA methylation and non-coding RNAs. In this review, we will discuss the role of epigenetic factors including chromatin, chromatin remodelers, DNA methyltransferases, and microRNAs in the context of alternative splicing, and discuss their potential involvement in alternative splicing during the EMT process.

Keywords: EMT; TEM; alternative splicing; cancer; chromatin; chromatine; epigenetics; épigénétique; épissage alternatif.

Figure 1. Interplay between chromatin remodelers, RNA Pol II and the splicing machinery during EMT

The kinetic model of alternative splicing posits that the spliceosome cannot keep up with the fast-moving RNA Pol II, therefore it has to choose between the splice sites presented to it and exon 2 (in this example) gets excluded. On the other hand, DNA methylation (represented by black lollipops), nucleosome positioning or histone modification changes, or microRNAs can all influence the rate of RNA Pol II elongation, slowing it down so that the spliceosome can now keep up with transcription. This results in all the exons being included. During EMT, many different types of slicing events can occur.

Figure 2. Examples of some splicing events during EMT

During EMT, many different types of slicing events occur. For example, p120 catenin switches from a short form to a longer form that includes additional exons. FGFR2 switches between isoforms containing two mutually exclusive exons, Exon IIIb or IIIc. CD44 produces multiple splice variants from 11 different exons, while after EMT, only the short variant (CD44s) is produced due to exon skipping.