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

Area of Science:

• Molecular Biology
• Genomics
• Post-transcriptional Regulation

Background:

• Over half of human genes utilize alternative cleavage and polyadenylation (ApA) to produce mRNA transcripts with varying 3' untranslated region (UTR) lengths.
• This variation influences mRNA fate and protein output, but the extent of 3' UTR diversity across tissues and the functional significance of ApA are not well understood.

Purpose of the Study:

• To quantitatively map 3' end transcriptome variations across diverse human tissues and isogenic systems using a novel sequencing method.
• To elucidate the distinct regulatory programs governing tissue-specific gene expression through 3' UTRs.

Main Methods:

• Development and application of a sequencing technique, termed 3'-seq, for precise mapping of mRNA 3' ends.
• Analysis of transcriptomic data from various human tissues and cellular systems undergoing transformation and differentiation.

Main Results:

• Identified two complementary programs for cell type-specific gene expression: tissue-restricted genes with single 3' UTRs and ubiquitously transcribed genes with multiple 3' UTRs.
• Observed that single-UTR genes primarily alter mRNA abundance, while multi-UTR genes predominantly modify 3' UTR isoform ratios for tissue specificity.
• Demonstrated that changes in 3' UTR ratios are largely independent of mRNA abundance shifts and target genes within specific cellular pathways.

Conclusions:

• Tissue-specific ApA site usage is a key mechanism for achieving cellular identity, primarily through differential regulation of 3' UTR isoforms in multi-UTR genes.
• ApA-mediated 3' UTR length variations modulate the targeting of microRNAs, contributing to cell-type-specific gene expression landscapes.