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

Buki Kwon, Mervin M. Fansler, Neil D. Patel, Jihye Lee, Weirui Ma and Christine Mayr ()
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Buki Kwon: Memorial Sloan Kettering Cancer Center
Mervin M. Fansler: Memorial Sloan Kettering Cancer Center
Neil D. Patel: Memorial Sloan Kettering Cancer Center
Jihye Lee: Memorial Sloan Kettering Cancer Center
Weirui Ma: Memorial Sloan Kettering Cancer Center
Christine Mayr: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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-κB 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.

Date: 2022
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DOI: 10.1038/s41467-022-30525-y

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