Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.17.254193v1?rss=1 Authors: Kwon, B., Patel, N. D., Lee, S.-H., Lee, J., Ma, W., Mayr, C. Abstract: Enhancers are DNA elements that increase gene expression. mRNA production is determined by transcript production and polyadenylation site (PAS) cleavage activity. We established an assay to measure enhancer-dependent PAS cleavage activity in human cells because PAS cleavage may control alternative 3'UTR isoform expression. We found that enhancers are widespread regulators of PAS cleavage and consistently increase cleavage of proximal and weak PAS. Half of tested transcription factors exclusively regulated PAS cleavage without affecting transcript production, whereas co-activators changed both parameters. Deletion of an endogenous enhancer of PTEN did not change gene-level mRNA or protein abundance but affected expression of alternative mRNA transcripts, thus preventing 3'UTR shortening. Our data reveal that in addition to controlling transcript production, enhancers also regulate PAS cleavage, thus changing 3'UTR isoform usage and protein activity, as PTEN proteins translated from the alternative 3'UTR isoforms differ in intrinsic lipid phosphatase activity despite having identical amino acid sequences. Copy rights belong to original authors. Visit the link for more info