The Crosstalk Between Epigenetic Mechanisms and Alternative RNA Processing Regulation

Abstract

As a co-transcriptional process, RNA processing, including alternative splicing and alternative polyadenylation, is crucial for the generation of multiple mRNA isoforms. RNA processing mechanisms are widespread across all higher eukaryotes and play critical roles in cell differentiation, organ development and disease response. Recently, significant progresses have been made in understanding the mechanism of RNA processing. RNA processing is regulated by trans-acting factors such as splicing factors, RNA-binding proteins and cis-sequences in pre-mRNA, and increasing evidence suggests that epigenetic mechanisms, which are important for the dynamic regulation and state of specific chromatic regions, are also involved in co-transcriptional RNA processing. In contrast, recent studies also suggest that alternative RNA processing also has a feedback regulation on epigenetic mechanisms. In this review, we discuss recent studies and summarize the current knowledge on the epigenetic regulation of alternative RNA processing. In addition, a feedback regulation of RNA processing on epigenetic regulators is also discussed.

Keywords: DNA methylation; RNA processing; alternative polyadenylation; alternative splicing; epigenetics; histone modifications.

FIGURE 1

A proposed model for chromatin-based epigenetic regulation of alternative RNA processing. (A) A proposed model of chromatin-based regulation of alternative splicing in mammals. Adaptor proteins recognizes and binds to alternative exon, which is marked by epigenetic marks (such as 5mC and histone modifications), to affect alternative splicing through two possible mechanisms: (1) Adaptor protein recruits chromatin regulators (such as chromatin remodelers, cohesion complex, etc.) to change the chromatin status of alternative exon, leading to a stalling of Pol II elongation, which in turn favors the retention of alternative exon. (2) Adaptor protein directly recruits splicing-related factors to promote the retention of alternative exon. (B) A proposed model of chromatin-based regulation of alternative polyadenylation in plants. The ASI1-AIPP1-EDM2 (AAE) complex recognizes and binds to the intronic heterochromatin elements (such as 5mC and H3K9me2) and corresponding pre-mRNA, favoring the passthrough of elongating Pol II, thereby promoting the usage of distal polyadenylation signal. When the AAE complex is absent, Pol II elongation is slowed down at intronic heterochromatin region, which favors the usage of proximal polyadenylation signal. Different colored boxes in (A) and (B) represent exons.

FIGURE 2

A proposed model for non-coding RNA (ncRNA)-mediated regulation of alternative RNA processing. (A) ncRNA directly interacts with different splicing factor to influence alternative RNA processing through two possible mechanisms: ncRNA-splicing factor complex recognizes and binds to the junction region of intron and alternative exon to promote the retention of alternative exon. ncRNA can also inhibit the targeting of splicing factor to the splicing site of pre-mRNA. Asterisks represent polyadenylation signals. Rectangular boxes represent exons. (B) ncRNA recognizes and binds to polyadenylation signal-flanking sequence of pre-mRNA, which prevents the accession of polyadenylation-related factors, thereby leading to the usage of distal polyadenylation signal. Different colored boxes in (A) and (B) represent exons.