Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

Multi-UTR genes are widely transcribed and express their alternative 3 ' UTR isoforms in a cell type-specific manner. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate 3 ' UTR isoform expression. Endogenous enhancer deletion of the multi-UTR gene PTEN did not impair transcript production but prevented 3 ' UTR isoform switching which was recapitulated by silencing of an enhancer-bound transcription factor. In reporter assays, enhancers increase transcript production when paired with single-UTR gene promoters. However, when combined with multi-UTR gene promoters, they change 3 ' UTR isoform expression by increasing 3 ' end processing activity of polyadenylation sites. Processing activity of polyadenylation sites is affected by transcription factors, including NF-kappa B and MYC, transcription elongation factors, chromatin remodelers, and histone acetyltransferases. As endogenous cell type-specific enhancers are associated with genes that increase their short 3 ' UTRs in a cell type-specific manner, our data suggest that transcriptional enhancers integrate cellular signals to regulate cell type-and condition-specific 3 ' UTR isoform expression. Transcriptional enhancers are known to regulate transcript production. Here, the authors show that transcription factors that bind to enhancers also regulate polyadenylation site cleavage activity, thus changing expression of alternative 3' UTRs.