Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression

TLDR

More than half of human genes use alternative cleavage and polyadenylation to generate mRNA transcripts with variable 3′ UTR lengths, yet the tissue‑specific extent and functional role of this variation remain poorly understood. The study developed 3′‑seq to quantitatively map transcriptome 3′ ends across diverse human tissues and isogenic transformation systems. 3′‑seq quantitatively captures 3′ ends of transcripts, enabling detection of alternative polyadenylation events across tissues. Cell type‑specific expression is achieved by two complementary programs: tissue‑restricted genes use single 3′ UTRs, while ubiquitously transcribed genes generate multiple 3′ UTRs that shift isoform ratios during transformation and differentiation, and these tissue‑specific ApA changes alter microRNA targeting without global 3′ UTR length shifts.

Abstract

More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3′ untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3′ UTR variation across tissues and the functional role of ApA remain poorly understood. We developed a sequencing method called 3′-seq to quantitatively map the 3′ ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell type-specific gene expression is accomplished by two complementary programs. Tissue-restricted genes tend to have single 3′ UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3′ UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi-UTR genes mostly change 3′ UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3′ UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3′ UTR ratios; these changes in 3′ UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs.