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METTL3 regulates breast cancer-associated alternative splicing switches
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).ORCID iD: 0000-0003-0997-5958
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).ORCID iD: 0000-0002-5389-244x
Department of Molecular Biology and Genetics, University of Extremadura, Badajoz, Spain.
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2023 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 42, p. 911-925Article in journal (Refereed) Published
Abstract [en]

Alternative splicing (AS) enables differential inclusion of exons from a given transcript, thereby contributing to the transcriptome and proteome diversity. Aberrant AS patterns play major roles in the development of different pathologies, including breast cancer. N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, influences tumor progression and metastasis of breast cancer, and it has been recently linked to AS regulation. Here, we identify a specific AS signature associated with breast tumorigenesis in vitro. We characterize for the first time the role of METTL3 in modulating breast cancer-associated AS programs, expanding the role of the m6A-methyltransferase in tumorigenesis. Specifically, we find that both m6A deposition in splice site boundaries and in splicing and transcription factor transcripts, such as MYC, direct AS switches of specific breast cancer-associated transcripts. Finally, we show that five of the AS events validated in vitro are associated with a poor overall survival rate for patients with breast cancer, suggesting the use of these AS events as a novel potential prognostic biomarker.

Place, publisher, year, edition, pages
Nature Publishing Group, 2023. Vol. 42, p. 911-925
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology Cancer and Oncology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-194175DOI: 10.1038/s41388-023-02602-zISI: 000925962300003PubMedID: 36725888Scopus ID: 2-s2.0-85147175928OAI: oai:DiVA.org:umu-194175DiVA, id: diva2:1654300
Funder
Knut and Alice Wallenberg FoundationRegion VästerbottenSwedish Research Council, 2017-01636Swedish Cancer Society, 19 0337 PjThe Kempe Foundations, SMK-1766Cancerforskningsfonden i Norrland, LP 16-2126Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2024-04-08Bibliographically approved
In thesis
1. RNA-mediated gene expression regulation
Open this publication in new window or tab >>RNA-mediated gene expression regulation
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
RNA-medierad genuttrycksreglering
Abstract [en]

The regulation of gene expression is a key mechanism that underlies all biological processes, from embryonic development to the onset and progression of various diseases, including cancer. A growing body of evidence places RNA molecules at the center of critical regulatory steps in gene expression. They serve not only as intermediate molecules between DNA and proteins but also act as regulators of processes such as alternative splicing (AS) and translation, among others. This thesis focuses on the role of RNA in gene expression regulation. Specifically, it addresses how intrinsic properties of RNA, RNA chemical modifications, and RNA binding proteins (RBPs) can control gene expression regulatory processes.

The first part tackles specific aspects of AS in neurodifferentiation. Paper I shows how RBPs affect AS in mouse embryonic stem cells (ESCs). Within this work, we identified ZFP207, a known transcription factor (TF), as an RBP with a crucial role in modulating the AS of key transcripts for neurodifferentiation. Depletion of ZFP207 in mouse ESCs led to abnormal AS patterns and a differentiated cell phenotype.

The second part (Papers II-IV) focuses on the role of RNA modifications in disease. In Paper II, the publicly available literature linking deregulations of RNA modifications and their regulatory proteins with different diseases was curated. The obtained information was integrated into the 2021 update of the MODOMICS database, the most extensive RNA modifications database to date. Papers III and IV exemplify how two different RNA marks contribute to breast cancer. Paper III shows how METTL3, the enzyme responsible for N6-methyladenosine (m6A) deposition on messenger RNA (mRNA), affects tumorigenesis by modulating AS. METTL3-mediated AS regulation can be done either by depositing m6A at the intron-exon junctions of specific transcripts or on transcripts encoding for splicing and transcription factors, such as MYC. Changes in RNA modifications of ribosomal RNA (rRNA) affect stability, folding, and interactions with other molecules, leading to perturbed translation efficiency (TE). In Paper IV, we focused on the role of 2'-O-methylation, the most abundant rRNA modification, and its catalytic enzyme, fibrillarin (FBL), in triple-negative breast cancer (TNBC). We discovered that certain proto-oncogenes associated with breast cancer displayed a reduction in TE upon FBL depletion. Additionally, we identified 7 2'-O-methylation sites that might mediate TE regulation in a TNBC cellular model. Moreover, our study uncovered alterations in the ribosomal protein composition within the ribosomes of FBL-depleted cells. Our results support the pivotal role of 2'-O-methylation in controlling the translational capabilities of ribosomes in TNBC cells.

Overall, this work encompasses multiple aspects of gene expression regulation and describes how RNA modifications and RBPs modulate the fate of specific transcripts by controlling AS or translation.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 109
Series
Doctoral thesis / Umeå University, Department of Molecular Biology ; 2301
Keywords
RNA modifications, fibrillarin, 2'-O-methylation, translation, alternative splicing, METTL3, m6A, ZFP207, breast cancer, mouse ESCs
National Category
Basic Medicine
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-223013 (URN)978-91-8070-372-7 (ISBN)978-91-8070-371-0 (ISBN)
Public defence
2024-05-03, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (English)
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Available from: 2024-04-12 Created: 2024-04-08 Last updated: 2024-04-12Bibliographically approved

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Achour, CyrinneBhattarai, Devi PrasadGroza, PaulaAguilo, Francesca

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Achour, CyrinneBhattarai, Devi PrasadGroza, PaulaAguilo, Francesca
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