Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Aguilo, Francesca, PhDORCID iD iconorcid.org/0000-0002-2374-2045
Alternative names
Publications (10 of 32) Show all publications
Esteva-Socias, M. & Aguilo, F. (2024). METTL3 as a master regulator of translation in cancer: mechanisms and implications. NAR Cancer, 6(1), Article ID zcae009.
Open this publication in new window or tab >>METTL3 as a master regulator of translation in cancer: mechanisms and implications
2024 (English)In: NAR Cancer, E-ISSN 2632-8674, Vol. 6, no 1, article id zcae009Article in journal (Refereed) Published
Abstract [en]

Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m6A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m6A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m6A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m6A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.

Place, publisher, year, edition, pages
Oxford University Press, 2024
National Category
Biochemistry and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-222414 (URN)10.1093/narcan/zcae009 (DOI)38444581 (PubMedID)2-s2.0-85187108906 (Scopus ID)
Funder
EU, Horizon 2020, 956810Swedish Research Council, 2022-01322Swedish Cancer Society, 22 2455 Pj
Available from: 2024-03-22 Created: 2024-03-22 Last updated: 2024-03-22Bibliographically approved
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
Open this publication in new window or tab >>METTL3 regulates breast cancer-associated alternative splicing switches
Show others...
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
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology Cancer and Oncology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-194175 (URN)10.1038/s41388-023-02602-z (DOI)000925962300003 ()36725888 (PubMedID)2-s2.0-85147175928 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationRegion VästerbottenSwedish Research Council, 2017-01636Swedish Cancer Society, 19 0337 PjThe Kempe Foundations, SMK-1766Cancerforskningsfonden i Norrland, LP 16-2126
Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2024-04-08Bibliographically approved
Xu, A., Liu, M., Huang, M.-F., Zhang, Y., Hu, R., Gingold, J. A., . . . Lee, D.-F. (2023). Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation. Nature Communications, 14(1), Article ID 1694.
Open this publication in new window or tab >>Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
Show others...
2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 1694Article in journal (Refereed) Published
Abstract [en]

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-206456 (URN)10.1038/s41467-023-37398-9 (DOI)36973285 (PubMedID)2-s2.0-85150958732 (Scopus ID)
Available from: 2023-04-13 Created: 2023-04-13 Last updated: 2023-04-13Bibliographically approved
Bhattarai, D. P. & Aguilo, F. (2022). m6A RNA immunoprecipitation followed by high-throughput sequencing to map N6-Methyladenosine (3ed.). In: Erik Dassi (Ed.), Post-transcriptional gene regulation: (pp. 355-362). Humana Press
Open this publication in new window or tab >>m6A RNA immunoprecipitation followed by high-throughput sequencing to map N6-Methyladenosine
2022 (English)In: Post-transcriptional gene regulation / [ed] Erik Dassi, Humana Press, 2022, 3, , p. 8p. 355-362Chapter in book (Refereed)
Abstract [en]

N6-methyladenosine (m6A) is the most abundant internal modification on messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in eukaryotes. It influences gene expression by regulating RNA processing, nuclear export, mRNA decay, and translation. Hence, m6A controls fundamental cellular processes, and dysregulated deposition of m6A has been acknowledged to play a role in a broad range of human diseases, including cancer. m6A RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq or m6A-seq) is a powerful technique to map m6A in a transcriptome-wide level. After immunoprecipitation of fragmented polyadenylated (poly(A)+) rich RNA by using specific anti-m6A antibodies, both the immunoprecipitated RNA fragments together with the input control are subjected to massively parallel sequencing. The generation of such comprehensive methylation profiles of signal enrichment relative to input control is necessary in order to better comprehend the pathogenesis behind aberrant m6A deposition.

Place, publisher, year, edition, pages
Humana Press, 2022. p. 8 Edition: 3
Series
Methods in Molecular Biology (MIMB), ISSN 1064-3745, E-ISSN 1940-6029 ; 2404
Keywords
Epitranscriptomics, MeRIP-seq or m6A-seq, METTL3, N6-Methyladenosine
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-189549 (URN)10.1007/978-1-0716-1851-6_19 (DOI)2-s2.0-85118431040 (Scopus ID)9781071618516 (ISBN)9781071618509 (ISBN)
Funder
Region VästerbottenKnut and Alice Wallenberg FoundationSwedish Research Council, 2017-01636The Kempe Foundations, 19 0337 Pj, SMK-1766
Available from: 2021-11-16 Created: 2021-11-16 Last updated: 2022-03-08Bibliographically approved
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
Open this publication in new window or tab >>MODOMICS: a database of RNA modification pathways. 2021 update
Show others...
2022 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no D1, p. D231-D235Article in journal (Refereed) 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/.

Place, publisher, year, edition, pages
Oxford University Press, 2022
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:umu:diva-192884 (URN)10.1093/nar/gkab1083 (DOI)000743496700028 ()34893873 (PubMedID)2-s2.0-85125009611 (Scopus ID)
Funder
EU, Horizon 2020, 956810Knut and Alice Wallenberg FoundationSwedish Cancer Society, 190337Cancerforskningsfonden i Norrland, AMP 21-1030
Note

Issue Section: Database Issue

Available from: 2022-03-08 Created: 2022-03-08 Last updated: 2024-04-08Bibliographically approved
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.
Open this publication in new window or tab >>ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
Show others...
2022 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 23, no 3, article id e53191Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-191672 (URN)10.15252/embr.202153191 (DOI)000743102200001 ()35037361 (PubMedID)2-s2.0-85122763926 (Scopus ID)
Available from: 2022-01-21 Created: 2022-01-21 Last updated: 2024-04-08Bibliographically approved
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
Open this publication in new window or tab >>A mark of disease: How mRNA modifications shape genetic and acquired pathologies
Show others...
2021 (English)In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 27, no 4, p. 367-389Article, review/survey (Refereed) 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.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press (CSHL), 2021
Keywords
Cancer, Epitranscriptomics, Human disease, mRNA, Posttranscriptional regulation of gene expression, RNA modifications
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-182007 (URN)10.1261/rna.077271.120 (DOI)000629533500002 ()2-s2.0-85103017419 (Scopus ID)
Available from: 2021-04-06 Created: 2021-04-06 Last updated: 2023-09-05Bibliographically approved
Relier, S., Ripoll, J., Guillorit, H., Amalric, A., Achour, C., Boissière, F., . . . David, A. (2021). FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell. Nature Communications, 12(1), Article ID 1716.
Open this publication in new window or tab >>FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
Show others...
2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 1716Article in journal (Refereed) Published
Abstract [en]

Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N6,2’-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-181801 (URN)10.1038/s41467-021-21758-4 (DOI)000631927600001 ()2-s2.0-85102687058 (Scopus ID)
Available from: 2021-03-30 Created: 2021-03-30 Last updated: 2023-09-05Bibliographically approved
Martinez-Gamero, C., Malla, S. & Aguilo, F. (2021). LSD1: Expanding functions in stem cells and differentiation. Cells, 10(11), Article ID 3252.
Open this publication in new window or tab >>LSD1: Expanding functions in stem cells and differentiation
2021 (English)In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3252Article, review/survey (Refereed) Published
Abstract [en]

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity during mammalian development. Histone methylation governs gene expression programs that play a key role in the regulation of the balance between self-renewal and differentiation of ESCs. Lysine-specific deme-thylase 1 (LSD1, also known as KDM1A), the first identified histone lysine demethylase, demethyl-ates H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. Moreover, it has also been shown to demethylate non-histone substrates playing a central role in the regulation of nu-merous cellular processes. In this review, we summarize current knowledge about LSD1 and the molecular mechanism by which LSD1 influences the stem cells state, including the regulatory cir-cuitry underlying self-renewal and pluripotency.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Differentiation, Embryonic stem cells, Epigenetics, Histone methylation, Induced pluripotent stem cells, KDM1A, LSD1, Lysine-specific demethylase, Non-his-tone substrate, Pluripotency, Self-renewal
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-189925 (URN)10.3390/cells10113252 (DOI)000724414100001 ()34831474 (PubMedID)2-s2.0-85119274398 (Scopus ID)
Available from: 2021-11-29 Created: 2021-11-29 Last updated: 2023-09-05Bibliographically approved
Kumari, K., Groza, P. & Aguilo, F. (2021). Regulatory roles of RNA modifications in breast cancer. NAR Cancer, 3(3), Article ID zcab036.
Open this publication in new window or tab >>Regulatory roles of RNA modifications in breast cancer
2021 (English)In: NAR Cancer, E-ISSN 2632-8674, Vol. 3, no 3, article id zcab036Article, review/survey (Refereed) 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.

Place, publisher, year, edition, pages
Oxford University Press, 2021
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-202959 (URN)10.1093/narcan/zcab036 (DOI)000925411800012 ()34541538 (PubMedID)2-s2.0-85126281516 (Scopus ID)
Available from: 2023-01-14 Created: 2023-01-14 Last updated: 2023-09-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2374-2045

Search in DiVA

Show all publications