RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 Sep 12

PMID 31509743

Citations 24

Authors

Rakesh Chatrikhi

Michael J Mallory

Matthew R Gazzara

Laura M Agosto

Wandi S Zhu

Adam J Litterman

K Mark Ansel

Kristen W Lynch

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML.

Brunmeir R, Ying L, Yan J, Hee Y, Lin B, Kaur H Leukemia. 2025; 39(3):650-662.

PMID: 39774797 PMC: 11879851. DOI: 10.1038/s41375-024-02509-y.

binds to CELF2 in newly diagnosed multiple myeloma promoting short progression-free survival to standard therapy.

Mishra R, Thunuguntla P, Perkin A, Duraiyan D, Bagwill K, Gonzales S bioRxiv. 2024; .

PMID: 38979159 PMC: 11230414. DOI: 10.1101/2024.06.27.600975.

Alternative 3'UTR expression induced by T cell activation is regulated in a temporal and signal dependent manner.

Blake D, Gazzara M, Breuer I, Ferretti M, Lynch K Sci Rep. 2024; 14(1):10987.

PMID: 38745101 PMC: 11094061. DOI: 10.1038/s41598-024-61951-1.

Regulation and function of alternative polyadenylation in development and differentiation.

Gallicchio L, Olivares G, Berry C, Fuller M RNA Biol. 2023; 20(1):908-925.

PMID: 37906624 PMC: 10730144. DOI: 10.1080/15476286.2023.2275109.

RNA circuits and RNA-binding proteins in T cells.

Zhu W, Wheeler B, Ansel K Trends Immunol. 2023; 44(10):792-806.

PMID: 37599172 PMC: 10890840. DOI: 10.1016/j.it.2023.07.006.

References

Lynch K, Weiss A . A model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates protein kinase C and Ras. Mol Cell Biol. 1999; 20(1):70-80. PMC: 85051. DOI: 10.1128/MCB.20.1.70-80.2000. View

Ladd A, Charlet N, Cooper T . The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol. 2001; 21(4):1285-96. PMC: 99581. DOI: 10.1128/MCB.21.4.1285-1296.2001. View

Rothrock C, Cannon B, Hahm B, Lynch K . A conserved signal-responsive sequence mediates activation-induced alternative splicing of CD45. Mol Cell. 2003; 12(5):1317-24. DOI: 10.1016/s1097-2765(03)00434-9. View

Tian B, Hu J, Zhang H, Lutz C . A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res. 2005; 33(1):201-12. PMC: 546146. DOI: 10.1093/nar/gki158. View

Lejeune F, Maquat L . Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol. 2005; 17(3):309-15. DOI: 10.1016/j.ceb.2005.03.002. View

Melton A, Jackson J, Wang J, Lynch K . Combinatorial control of signal-induced exon repression by hnRNP L and PSF. Mol Cell Biol. 2007; 27(19):6972-84. PMC: 2099238. DOI: 10.1128/MCB.00419-07. View

Sandberg R, Neilson J, Sarma A, Sharp P, Burge C . Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites. Science. 2008; 320(5883):1643-7. PMC: 2587246. DOI: 10.1126/science.1155390. View

Topp J, Jackson J, Melton A, Lynch K . A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA. 2008; 14(10):2038-49. PMC: 2553740. DOI: 10.1261/rna.1212008. View

Bartel D . MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136(2):215-33. PMC: 3794896. DOI: 10.1016/j.cell.2009.01.002. View

10.

Dembowski J, Grabowski P . The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS Genet. 2009; 5(8):e1000595. PMC: 2715136. DOI: 10.1371/journal.pgen.1000595. View

11.

Ji Z, Tian B . Reprogramming of 3' untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLoS One. 2009; 4(12):e8419. PMC: 2791866. DOI: 10.1371/journal.pone.0008419. View

12.

Yang Q, Gilmartin G, Doublie S . Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3' processing. Proc Natl Acad Sci U S A. 2010; 107(22):10062-7. PMC: 2890493. DOI: 10.1073/pnas.1000848107. View

13.

Dujardin G, Buratti E, Charlet-Berguerand N, Martins de Araujo M, Mbopda A, Le Jossic-Corcos C . CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3. Nucleic Acids Res. 2010; 38(20):7273-85. PMC: 2978352. DOI: 10.1093/nar/gkq573. View

14.

Mallory M, Jackson J, Weber B, Chi A, Heyd F, Lynch K . Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2. Mol Cell Biol. 2011; 31(11):2184-95. PMC: 3133246. DOI: 10.1128/MCB.05170-11. View

15.

Sheets M, Ogg S, Wickens M . Point mutations in AAUAAA and the poly (A) addition site: effects on the accuracy and efficiency of cleavage and polyadenylation in vitro. Nucleic Acids Res. 1990; 18(19):5799-805. PMC: 332317. DOI: 10.1093/nar/18.19.5799. View

16.

Basu S, Malik R, Huggins C, Lee S, Sebastian T, Sakchaisri K . 3'UTR elements inhibit Ras-induced C/EBPβ post-translational activation and senescence in tumour cells. EMBO J. 2011; 30(18):3714-28. PMC: 3173785. DOI: 10.1038/emboj.2011.250. View

17.

DasGupta T, Ladd A . The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdiscip Rev RNA. 2011; 3(1):104-21. PMC: 3243963. DOI: 10.1002/wrna.107. View

18.

Masuda A, Andersen H, Doktor T, Okamoto T, Ito M, Andresen B . CUGBP1 and MBNL1 preferentially bind to 3' UTRs and facilitate mRNA decay. Sci Rep. 2012; 2:209. PMC: 3250574. DOI: 10.1038/srep00209. View

19.

Derti A, Garrett-Engele P, MacIsaac K, Stevens R, Sriram S, Chen R . A quantitative atlas of polyadenylation in five mammals. Genome Res. 2012; 22(6):1173-83. PMC: 3371698. DOI: 10.1101/gr.132563.111. View

20.

Martin G, Gruber A, Keller W, Zavolan M . Genome-wide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length. Cell Rep. 2012; 1(6):753-63. DOI: 10.1016/j.celrep.2012.05.003. View