| Summary: | Summary: The 3′ UTR (UTR) of human mRNAs plays a critical role in controlling protein expression and function. Importantly, 3′ UTRs of human messages are not invariant for each gene but rather are shaped by alternative polyadenylation (APA) in a cell state-dependent manner, including in response to T cell activation. However, the proteins and mechanisms driving APA regulation remain poorly understood. Here we show that the RNA-binding protein CELF2 controls APA of its own message in a signal-dependent manner by competing with core enhancers of the polyadenylation machinery for binding to RNA. We further show that CELF2 binding overlaps with APA enhancers transcriptome-wide, and almost half of 3′ UTRs that undergo T cell signaling-induced APA are regulated in a CELF2-dependent manner. These studies thus reveal CELF2 to be a critical regulator of 3′ UTR identity in T cells and demonstrate an additional mechanism for CELF2 in regulating polyadenylation site choice. : Alternative polyadenylation (APA) is broadly regulated during cellular activation. Chatrikhi et al. demonstrate that the RNA-binding protein CELF2 competes with CFIm25 and CstF64 for binding around polyadenylation sites. Increased expression of CELF2 upon cellular activation alters this competition and is a key driver of activation-induced APA. Keywords: CELF2, CFIm25, CstF64, polyadenylation, APA, 3′ UTR
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