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RNA-mediated gene expression regulation
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). (Francesca Aguilo)ORCID-id: 0000-0002-5389-244x
2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
RNA-medierad genuttrycksreglering (Svenska)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2024. , s. 109
Serie
Doctoral thesis / Umeå University, Department of Molecular Biology ; 2301
Nyckelord [en]
RNA modifications, fibrillarin, 2'-O-methylation, translation, alternative splicing, METTL3, m6A, ZFP207, breast cancer, mouse ESCs
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-223013ISBN: 978-91-8070-372-7 (digital)ISBN: 978-91-8070-371-0 (tryckt)OAI: oai:DiVA.org:umu-223013DiVA, id: diva2:1849434
Disputation
2024-05-03, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2024-04-12 Skapad: 2024-04-08 Senast uppdaterad: 2024-04-12Bibliografiskt granskad
Delarbeten
1. ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
Öppna denna publikation i ny flik eller fönster >>ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
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2022 (Engelska)Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 23, nr 3, artikel-id e53191Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The pluripotent state is not solely governed by the action of the core transcription factors OCT4, SOX2, and NANOG, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize its role in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, mouse ZFP207 does not transcriptionally regulate neuronal and stem cell-related genes but exerts its effects by controlling AS networks and by acting as an RBP. Our study expands the role of ZFP207 in maintaining ESC identity, and underscores the functional versatility of ZFP207 in regulating neural fate commitment.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2022
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-191672 (URN)10.15252/embr.202153191 (DOI)000743102200001 ()35037361 (PubMedID)2-s2.0-85122763926 (Scopus ID)
Tillgänglig från: 2022-01-21 Skapad: 2022-01-21 Senast uppdaterad: 2024-04-08Bibliografiskt granskad
2. MODOMICS: a database of RNA modification pathways. 2021 update
Öppna denna publikation i ny flik eller fönster >>MODOMICS: a database of RNA modification pathways. 2021 update
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2022 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, nr D1, s. D231-D235Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2022
Nationell ämneskategori
Biokemi och molekylärbiologi Bioinformatik och systembiologi
Identifikatorer
urn:nbn:se:umu:diva-192884 (URN)10.1093/nar/gkab1083 (DOI)000743496700028 ()34893873 (PubMedID)2-s2.0-85125009611 (Scopus ID)
Forskningsfinansiär
EU, Horisont 2020, 956810Knut och Alice Wallenbergs StiftelseCancerfonden, 190337Cancerforskningsfonden i Norrland, AMP 21-1030
Anmärkning

Issue Section: Database Issue

Tillgänglig från: 2022-03-08 Skapad: 2022-03-08 Senast uppdaterad: 2024-04-08Bibliografiskt granskad
3. METTL3 regulates breast cancer-associated alternative splicing switches
Öppna denna publikation i ny flik eller fönster >>METTL3 regulates breast cancer-associated alternative splicing switches
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2023 (Engelska)Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 42, s. 911-925Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2023
Nationell ämneskategori
Biokemi och molekylärbiologi Bioinformatik och systembiologi Cancer och onkologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-194175 (URN)10.1038/s41388-023-02602-z (DOI)000925962300003 ()36725888 (PubMedID)2-s2.0-85147175928 (Scopus ID)
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseRegion VästerbottenVetenskapsrådet, 2017-01636Cancerfonden, 19 0337 PjKempestiftelserna, SMK-1766Cancerforskningsfonden i Norrland, LP 16-2126
Tillgänglig från: 2022-04-26 Skapad: 2022-04-26 Senast uppdaterad: 2024-04-08Bibliografiskt granskad
4. Fibrillarin regulates oncogenic protein pools and ribosome protein composition in triple-negative breast cancer
Öppna denna publikation i ny flik eller fönster >>Fibrillarin regulates oncogenic protein pools and ribosome protein composition in triple-negative breast cancer
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-223012 (URN)
Tillgänglig från: 2024-04-08 Skapad: 2024-04-08 Senast uppdaterad: 2024-04-08

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Publikationen är tillgänglig i fulltext från 2025-05-03 07:00
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Groza, Paula Petronela

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