Miller, Z. D.; Dearborn, J.; Barrantes-Reynolds, R.; Paculova, H.; Honson, D.; Sha, J.; Deng, W.; Kirch, T.; Dowell, W.; Languon, S.; Freeman, K.; Frietze, S.; Wohlschlegel, J.; MAJUMDAR, D.

Alternative polyadenylation is a mechanism by which cells tune gene expression, and dysregulation can lead to development of disease. PABPC1 has been implicated in poly(A) site selection, but its function in gene regulation remains contradictory and poorly defined. Here, we investigate its role in B cell development, where APA controls immunoglobulin secretion. To define this role, we mapped PABPC1-RNA interactions using CLAP-seq and perturbed PABPC1 expression using a degron based strategy. PABPC1 localizes to the 3' UTR in 70% of its gene targets and primarily binds to A-rich regions. Integration with transcriptomic data suggests PABPC1 downregulates 60% of its gene targets. While transcriptome-wide shifts in 3' prime UTR length were limited, PABPC1 binding was specifically enriched in genes exhibiting significant 3' UTR shortening. Using a foundational genomics model, we find the PAS-proximal region is the most predictive of gene expression within PABPC1 binding sites. Positional analysis revealed PABPC1 localizes closer to the PAS in genes downregulated following depletion. In immunoglobulin transcripts, PABPC1 binds to both secreted and membrane isoforms and is more enriched at the secretory PAS, and depletion modestly alters immunoglobulin expression. Together, our findings demonstrate PABPC1 primarily shortens and downregulates its targets in a context dependent manner.