RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery
Rakesh Chatrikhi,
Michael J. Mallory,
Matthew R. Gazzara,
Laura M. Agosto,
Wandi S. Zhu,
Adam J. Litterman,
K. Mark Ansel,
Kristen W. Lynch
Affiliations
Rakesh Chatrikhi
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Michael J. Mallory
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Matthew R. Gazzara
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Laura M. Agosto
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Wandi S. Zhu
Department of Microbiology and Immunology, UC San Francisco, San Francisco, CA 94143, USA
Adam J. Litterman
Department of Microbiology and Immunology, UC San Francisco, San Francisco, CA 94143, USA
K. Mark Ansel
Department of Microbiology and Immunology, UC San Francisco, San Francisco, CA 94143, USA
Kristen W. Lynch
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
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