Alternative 3’UTRs Play a Widespread Role in Translation-Independent mRNA Association with Endoplasmic Reticulum

Abstract

Transcripts encoding membrane and secreted proteins undergo translation on endoplasmic reticulum (ER). Here, using cell fractionation, polysome profiling, and 3’ end sequencing, we examine translation-independent ER association (TiERA) of poly(A)+ RNAs. We show different functional gene groups have distinct TiERA potentials, and transcript size and sequence motifs are determinants of TiERA. Alternative polyadenylation (APA) isoforms differ substantially in TiERA, with long 3’UTR isoforms generally having a higher TiERA potential than short ones, highlighting a role of 3’UTR in TiERA control. The widespread 3’UTR lengthening in cell differentiation leads to greater transcript association with ER, especially for genes whose isoforms differ substantially in size. Moreover, TiERA inversely correlates with mRNA stability, suggesting distinct mRNA decay mechanisms on ER versus in cytosol. Together, our data indicate that transcript features diversify TiERA among genes, leading to distinct mRNA metabolism, and APA alters ER association of gene transcripts because of TiERA difference between isoforms.