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Groza, P. P. (2024). RNA-mediated gene expression regulation. (Doctoral dissertation). Umeå: Umeå University
Åpne denne publikasjonen i ny fane eller vindu >>RNA-mediated gene expression regulation
2024 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Alternativ tittel[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.

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2024. s. 109
Serie
Doctoral thesis / Umeå University, Department of Molecular Biology ; 2301
Emneord
RNA modifications, fibrillarin, 2'-O-methylation, translation, alternative splicing, METTL3, m6A, ZFP207, breast cancer, mouse ESCs
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-223013 (URN)978-91-8070-372-7 (ISBN)978-91-8070-371-0 (ISBN)
Disputas
2024-05-03, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2024-04-12 Laget: 2024-04-08 Sist oppdatert: 2024-04-12bibliografisk kontrollert
Achour, C., Bhattarai, D. P., Groza, P., Roman, Á.-C. & Aguilo, F. (2023). METTL3 regulates breast cancer-associated alternative splicing switches. Oncogene, 42, 911-925
Åpne denne publikasjonen i ny fane eller vindu >>METTL3 regulates breast cancer-associated alternative splicing switches
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2023 (engelsk)Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 42, s. 911-925Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2023
HSV kategori
Forskningsprogram
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 and Alice Wallenberg FoundationRegion VästerbottenSwedish Research Council, 2017-01636Swedish Cancer Society, 19 0337 PjThe Kempe Foundations, SMK-1766Cancerforskningsfonden i Norrland, LP 16-2126
Tilgjengelig fra: 2022-04-26 Laget: 2022-04-26 Sist oppdatert: 2024-04-08bibliografisk kontrollert
Boccaletto, P., Stefaniak, F., Ray, A., Cappannini, A., Mukherjee, S., Purta, E., . . . Bujnicki, J. M. (2022). MODOMICS: a database of RNA modification pathways. 2021 update. Nucleic Acids Research, 50(D1), D231-D235
Åpne denne publikasjonen i ny fane eller vindu >>MODOMICS: a database of RNA modification pathways. 2021 update
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2022 (engelsk)Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, nr D1, s. D231-D235Artikkel i tidsskrift (Fagfellevurdert) 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/.

sted, utgiver, år, opplag, sider
Oxford University Press, 2022
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-192884 (URN)10.1093/nar/gkab1083 (DOI)000743496700028 ()34893873 (PubMedID)2-s2.0-85125009611 (Scopus ID)
Forskningsfinansiär
EU, Horizon 2020, 956810Knut and Alice Wallenberg FoundationSwedish Cancer Society, 190337Cancerforskningsfonden i Norrland, AMP 21-1030
Merknad

Issue Section: Database Issue

Tilgjengelig fra: 2022-03-08 Laget: 2022-03-08 Sist oppdatert: 2024-04-08bibliografisk kontrollert
Malla, S., Bhattarai, D. P., Groza, P., Melguizo-Sanchis, D., Atanasoai, I., Martinez Gamero, C., . . . Aguilo, F. (2022). ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export. EMBO Reports, 23(3), Article ID e53191.
Åpne denne publikasjonen i ny fane eller vindu >>ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
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2022 (engelsk)Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 23, nr 3, artikkel-id e53191Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2022
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-191672 (URN)10.15252/embr.202153191 (DOI)000743102200001 ()35037361 (PubMedID)2-s2.0-85122763926 (Scopus ID)
Tilgjengelig fra: 2022-01-21 Laget: 2022-01-21 Sist oppdatert: 2024-04-08bibliografisk kontrollert
Destefanis, E., Avşar, G., Groza, P., Romitelli, A., Torrini, S., Pir, P., . . . Dassi, E. (2021). A mark of disease: How mRNA modifications shape genetic and acquired pathologies. RNA: A publication of the RNA Society, 27(4), 367-389
Åpne denne publikasjonen i ny fane eller vindu >>A mark of disease: How mRNA modifications shape genetic and acquired pathologies
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2021 (engelsk)Inngår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 27, nr 4, s. 367-389Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.

sted, utgiver, år, opplag, sider
Cold Spring Harbor Laboratory Press (CSHL), 2021
Emneord
Cancer, Epitranscriptomics, Human disease, mRNA, Posttranscriptional regulation of gene expression, RNA modifications
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-182007 (URN)10.1261/rna.077271.120 (DOI)000629533500002 ()2-s2.0-85103017419 (Scopus ID)
Tilgjengelig fra: 2021-04-06 Laget: 2021-04-06 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Kumari, K., Groza, P. & Aguilo, F. (2021). Regulatory roles of RNA modifications in breast cancer. NAR Cancer, 3(3), Article ID zcab036.
Åpne denne publikasjonen i ny fane eller vindu >>Regulatory roles of RNA modifications in breast cancer
2021 (engelsk)Inngår i: NAR Cancer, E-ISSN 2632-8674, Vol. 3, nr 3, artikkel-id zcab036Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Collectively referred to as the epitranscriptome, RNA modifications play important roles in gene expression control regulating relevant cellular processes. In the last few decades, growing numbers of RNA modifications have been identified not only in abundant ribosomal (rRNA) and transfer RNA (tRNA) but also in messenger RNA (mRNA). In addition, many writers, erasers and readers that dynamically regulate the chemical marks have also been characterized. Correct deposition of RNA modifications is prerequisite for cellular homeostasis, and its alteration results in aberrant transcriptional programs that dictate human disease, including breast cancer, the most frequent female malignancy, and the leading cause of cancer-related death in women. In this review, we emphasize the major RNA modifications that are present in tRNA, rRNA and mRNA. We have categorized breast cancer-associated chemical marks and summarize their contribution to breast tumorigenesis. In addition, we describe less abundant tRNA modifications with related pathways implicated in breast cancer. Finally, we discuss current limitations and perspectives on epitranscriptomics for use in therapeutic strategies against breast and other cancers.

sted, utgiver, år, opplag, sider
Oxford University Press, 2021
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-202959 (URN)10.1093/narcan/zcab036 (DOI)000925411800012 ()34541538 (PubMedID)2-s2.0-85126281516 (Scopus ID)
Tilgjengelig fra: 2023-01-14 Laget: 2023-01-14 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Groza, P., Kumari, K., Destefanis, E., Williams, C., Marchand, V., Motorin, Y., . . . Aguilo, F. Fibrillarin regulates oncogenic protein pools and ribosome protein composition in triple-negative breast cancer.
Åpne denne publikasjonen i ny fane eller vindu >>Fibrillarin regulates oncogenic protein pools and ribosome protein composition in triple-negative breast cancer
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(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-223012 (URN)
Tilgjengelig fra: 2024-04-08 Laget: 2024-04-08 Sist oppdatert: 2024-04-08
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-5389-244x