The eukaryotic translation initiation factor eIF4E reprograms alternative splicing. (27th February 2023)

• Record Type: Journal Article
• Authors: Ghram, Mehdi; Morris, Gavin; Culjkovic‐Kraljacic, Biljana; Mars, Jean‐Clement; Gendron, Patrick; Skrabanek, Lucy; Revuelta, Maria Victoria; Cerchietti, Leandro; Guzman, Monica L; Borden, Katherine L B
• Is Part Of: EMBO journal. Volume 42:Number 7(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-27
• Subjects: acute myeloid leukemia -- eIF4E -- splicing; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021110496
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Aberrant splicing is typically attributed to splice‐factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation‐independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice‐factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice‐site selection for ~800 transcripts in cell lines and ~4, 600 transcripts in specimens from high‐eIF4E AML patients otherwise harboring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses, and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. By contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre‐mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in the case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation. Synopsis: Aberrant splicing in diseases such as AML is typically attributed to splice‐factor (SF) mutation or dysregulation of specific splicing factors. Here, eukaryotic translation initiation factor eIF4E is reported to induce broad‐range alternative splicing by simultaneously affecting multiple splicing factors. eIF4E induces the production of several SFs simultaneously by promoting nuclear mRNA export and directly interacting with a subset of pre‐mRNAs. A separation‐of‐function mutant of eIF4E shows that the loss of nuclear export activity severely impairs SF production. eIF4E physically associates with several components of the major spliceosome complexes. eIF4E interaction with RNAs is predominantly mediated by the m7G cap. eIF4E overexpression does not lead to global transcriptomic changes but alters splice‐site selection for thousands of transcripts in cell lines and AML patient specimens. eIF4E‐dependent splicing is dysregulated in primary high‐eIF4E AML patient samples. Abstract : Elevated expression of eIF4E leads to widescale changes in alternative splicing in the absence of splice‐factor mutations.