Crosstalk Between mRNA 3'-End Processing and Epigenetics

Abstract

The majority of eukaryotic genes produce multiple mRNA isoforms by using alternative poly(A) sites in a process called alternative polyadenylation (APA). APA is a dynamic process that is highly regulated in development and in response to extrinsic or intrinsic stimuli. Mis-regulation of APA has been linked to a wide variety of diseases, including cancer, neurological and immunological disorders. Since the first example of APA was described 40 years ago, the regulatory mechanisms of APA have been actively investigated. Conventionally, research in this area has focused primarily on the roles of regulatory cis-elements and trans-acting RNA-binding proteins. Recent studies, however, have revealed important functions for epigenetic mechanisms, including DNA and histone modifications and higher-order chromatin structures, in APA regulation. Here we will discuss these recent findings and their implications for our understanding of the crosstalk between epigenetics and mRNA 3'-end processing.

Keywords: chromatin; epigenetics; histone; mRNA 3' processing; polyadenylation.

Figure 1

Alternative Polyadenylation (APA) can, but does not always, change the coding sequence of the resulting mRNA transcript. (A) APA within the terminal exon does not change the coding sequence. The poly(A) tail is shown as AAAAA and splicing is shown as dashed lines. Selection of the proximal poly(A) site (PAS) or distal PAS results in the production of mRNA isoforms with different 3'untranslated regions (3'UTRs). These mRNAs may be subject to different regulation but code for identical proteins during translation. (B) Alternative polyadenylation (APA) upstream of the terminal exon changes the coding sequence. The poly(A) tail is shown as AAAAA and splicing is shown as dashed lines. In the first mRNA shown, selection of the intronic PAS results in an mRNA that will produce a truncated protein if translated. This truncated protein may not be functional, which can be used to repress gene expression. In the middle mRNA isoform, selection of an alternative PAS within an alternative exon results in exclusion of the downstream exon. As a result, this mRNA isoform has a different coding sequence than the final mRNA isoform, which could produce two proteins with alternative functions.

Figure 2

(A) A model of APA regulation by DNA methylation. DNA is wrapped around nucleosomes (purple). In the top example, an unmethylated intronic CpG island allows the Cohesin-CTCF complex to bind downstream of an intronic PAS. The PAS are represented by AATAAA. Cohesin-CTCF binding to DNA forms a DNA loop and enhances RNA Polymerase II (RNAPII) pausing. This increases usage of the intronic PAS. In the bottom example, the intronic CpG island is highly methylated and the Cohesin-CTCF complex cannot bind. As a result, RNAPII does not pause downstream of the intronic PAS, the intron is removed by splicing, and the downstream PAS is selected in the terminal exon. (B) A model of APA regulation by the AAE complex. In the top example, intronic heterochromatin leads to RNAPII pausing in the absence of the AAE complex. This increases usage of the intronic PAS. In the bottom example, the AAE complex binds the heterochromatic region and counteracts the effects of heterochromatin on RNAPII pausing. RNAPII then transcribes the downstream PAS and this PAS is recognized and selected by the mRNA 3'-end processing machinery.