title: Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling.
abstract: Studies in several cell types have highlighted dramatic and diverse changes in mRNA processing that occur upon cellular stimulation. However, the mechanisms and pathways that lead to regulated changes in mRNA processing remain poorly understood. Here we demonstrate that expression of the splicing factor CELF2 (CUGBP, Elav-like family member 2) is regulated in response to T-cell signaling through combined increases in transcription and mRNA stability. Transcriptional induction occurs within 6 h of stimulation and is dependent on activation of NF-κB. Subsequently, there is an increase in the stability of the CELF2 mRNA that correlates with a change in CELF2 3'UTR length and contributes to the total signal-induced enhancement of CELF2 expression. Importantly, we uncover dozens of splicing events in cultured T cells whose changes upon stimulation are dependent on CELF2 expression, and provide evidence that CELF2 controls a similar proportion of splicing events during human thymic T-cell development. Taken together, these findings expand the physiologic impact of CELF2 beyond that previously documented in developing neuronal and muscle cells to T-cell development and function, identify unappreciated instances of alternative splicing in the human thymus, and uncover novel mechanisms for CELF2 regulation that may broadly impact CELF2 expression across diverse cell types.
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Michael J
authors: MJ
authors: Mallory
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Samuel J
authors: SJ
authors: Allon
authors: Department of Cell and Molecular Medicine, University of California, San Diego, CA 92093.
authors: Jinsong
authors: J
authors: Qiu
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Matthew R
authors: MR
authors: Gazzara
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Iulia
authors: I
authors: Tapescu
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Nicole M
authors: NM
authors: Martinez
authors: Department of Cell and Molecular Medicine, University of California, San Diego, CA 92093.
authors: Xiang-Dong
authors: XD
authors: Fu
authors: Departments of Biochemistry and Biophysics and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and klync@mail.med.upenn.edu.
authors: Kristen W
authors: KW
authors: Lynch
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology*; D017398:Alternative Splicing / Q000502:physiology*; D000067878:CELF Proteins; D006801:Humans; D019169:Jurkat Cells; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020871:RNA Stability / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000067878:CELF Proteins; C117363:CELF2 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins
keywords: CELF2; T cells; alternative splicing; mRNA stability; thymic development