The differential expression of alternatively polyadenylated transcripts is a common stress-induced response mechanism that modulates mammalian mRNA expression in a quantitative and qualitative fashion

Abstract

Stress adaptation plays a pivotal role in biological processes and requires tight regulation of gene expression. In this study, we explored the effect of cellular stress on mRNA polyadenylation and investigated the implications of regulated polyadenylation site usage on mammalian gene expression. High-confidence polyadenylation site mapping combined with global pre-mRNA and mRNA expression profiling revealed that stress induces an accumulation of genes with differentially expressed polyadenylated mRNA isoforms in human cells. Specifically, stress provokes a global trend in polyadenylation site usage toward decreased utilization of promoter-proximal poly(A) sites in introns or ORFs and increased utilization of promoter-distal polyadenylation sites in intergenic regions. This extensively affects gene expression beyond regulating mRNA abundance by changing mRNA length and by altering the configuration of open reading frames. Our study highlights the impact of posttranscriptional mechanisms on stress-dependent gene regulation and reveals the differential expression of alternatively polyadenylated transcripts as a common stress-induced mechanism in mammalian cells.

Cleavage and polyadenylation: Ending the message expands gene regulation

“… 155,156 While no clear trend toward shortening or lengthening in UTR-APA has been observed, intronic pA sites are suppressed upon exposure to stress. 157 …”

Alternative polyadenylation and the stress response

“…The functional consequence of these elongation events in this study was broad affecting different characteristics of target transcripts. Interestingly, the stress‐induced transcript elongation observed did not have a major effect on transcript abundances, as only a limited number of alternatively polyadenylated transcripts experienced differential stability (Hollerer et al, ). This is consistent with findings of studies demonstrating that there is no correlation between transcript length and stability (Gruber et al, ; Spies, Burge, & Bartel, ).…”

“…This is consistent with findings of studies demonstrating that there is no correlation between transcript length and stability (Gruber et al, ; Spies, Burge, & Bartel, ). In fact, many of the elongated transcripts encoded full‐length proteins with added domains or extended 3′ UTRs that were believed to harbor different regulatory elements, such as miRNA binding sites (Hollerer et al, ). Due to inhibition of cap‐dependent translation during stress, it was hypothesized that the protein products encoded by many of these elongated transcripts played a role in the recovery of cells after stress has subsided and not the immediate responses of cells (Hollerer et al, ).…”

HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

“…In particular, recent data reveal that alternative polyadenylation is affected by cellular stresses, such as cold or heat shock and UV irradiation (23)(24)(25)(26)(39)(40)(41)(42). It is also known that alternative polyadenylation is influenced by treatment with anisomycin, which inhibits the peptidyl transferase activity of a ribosome (43,44). Therefore, our initial work was focused on a potential effect of cellular stresses on global alternative polyadenylation.…”