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Aguilo, Francesca, PhD
Alternative names
Publications (10 of 18) Show all publications
Malla, S., Melguizo-Sanchis, D. & Aguilo, F. (2019). Steering pluripotency and differentiation with N6-methyladenosine RNA modification. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, 1862(3), 394-402
Open this publication in new window or tab >>Steering pluripotency and differentiation with N6-methyladenosine RNA modification
2019 (English)In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, no 3, p. 394-402Article in journal (Refereed) Published
Abstract [en]

Chemical modifications of RNA provide a direct and rapid way to modulate the existing transcriptome, allowing the cells to adapt rapidly to the changing environment. Among these modifications, N6-methyladenosine (m6A) has recently emerged as a widely prevalent mark of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. m6A modification modulates a broad spectrum of biochemical processes, including mRNA decay, translation and splicing. Both m6A modification and the enzymes that control m6A metabolism are essential for normal development. In this review, we summarized the most recent findings on the role of m6A modification in maintenance of the pluripotency of embryonic stem cells (ESCs), cell fate specification, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), and differentiation of stem and progenitor cells.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Adipogenesis, Cellular differentiation, Embryonic stem cell, Epitranscriptomics, Hematopoietic stem cell, Induced pluripotent stem cell, METTL3, Myogenesis, N(6)-methyladenosine, Neurogenesis, RNA methylation, Spermatogenesis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153977 (URN)10.1016/j.bbagrm.2018.10.013 (DOI)000462104500017 ()30412796 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationVästerbotten County CouncilThe Kempe Foundations, JCK-1723.1Swedish Research Council, 2017-01636
Note

This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert

Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2019-04-12Bibliographically approved
Achour, C. & Aguilo, F. (2018). Long non-coding RNA and Polycomb: an intricate partnership in cancer biology. Frontiers in Bioscience, 23, 2106-2132
Open this publication in new window or tab >>Long non-coding RNA and Polycomb: an intricate partnership in cancer biology
2018 (English)In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 23, p. 2106-2132Article in journal (Refereed) Published
Abstract [en]

High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including X-inactive specific transcript (XIST), antisense non-coding RNA in the INK4 locus (ANRIL), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and HOX transcript antisense RNA (HOTAIR).

Keywords
cancer, lncRNA, Polycomb, XIST, ANRIL, HOTAIR, MALAT1, RNA modification, Review
National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-150389 (URN)10.2741/4693 (DOI)000439047100010 ()29772549 (PubMedID)
Available from: 2018-08-06 Created: 2018-08-06 Last updated: 2019-05-10Bibliographically approved
Aguilo, F., Zakirova, Z., Nolan, K., Wagner, R., Sharma, R., Hogan, M., . . . Ehrlich, M. E. (2017). THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation. Stem Cell Reports, 9(1), 92-107
Open this publication in new window or tab >>THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation
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2017 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 9, no 1, p. 92-107Article in journal (Refereed) Published
Abstract [en]

THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Developmental Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-137943 (URN)10.1016/j.stemcr.2017.04.032 (DOI)000405178400011 ()28579396 (PubMedID)
Available from: 2017-08-03 Created: 2017-08-03 Last updated: 2019-01-08Bibliographically approved
Aguilo, F. & Walsh, M. J. (2017). The N6-Methyladenosine RNA modification in pluripotency and reprogramming. Current Opinion in Genetics and Development, 46, 77-82
Open this publication in new window or tab >>The N6-Methyladenosine RNA modification in pluripotency and reprogramming
2017 (English)In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed) Published
Abstract [en]

Chemical modifications of RNA provide a direct and rapid way to manipulate the existing transcriptome, allowing rapid responses to the changing environment further enriching the regulatory capacity of RNA. N-6-Methyladenosine(m(6)A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. M(6)A modification affects a broad spectrum of cellular functions, including maintenance of the pluripotency of embryonic stem cells (ESCs) and the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the most recent findings on m(6)A modification with special focus on the different studies describing how m(6)A is implicated in ESC self-renewal, cell fate specification and iPSC generation.

Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-140886 (URN)10.1016/j.gde.2017.06.006 (DOI)000411955300011 ()28683341 (PubMedID)
Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2019-05-10Bibliographically approved
Rengasamy, M., Zhang, F., Vashisht, A., Song, W.-M., Aguilo, F., Sun, Y., . . . Walsh, M. J. (2017). The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer. Nucleic Acids Research, 45(19), 11106-11120
Open this publication in new window or tab >>The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 19, p. 11106-11120Article in journal (Refereed) Published
Abstract [en]

We observed overexpression and increased intranuclear accumulation of the PRMT5/WDR77 in breast cancer cell lines relative to immortalized breast epithelial cells. Utilizing mass spectrometry and biochemistry approaches we identified the Zn-finger protein ZNF326, as a novel interaction partner and substrate of the nuclear PRMT5/WDR77 complex. ZNF326 is symmetrically dimethylated at arginine 175 (R175) and this modification is lost in a PRMT5 and WDR77-dependent manner. Loss of PRMT5 or WDR77 in MDA-MB-231 cells leads to defects in alternative splicing, including inclusion of A-T rich exons in target genes, a phenomenon that has previously been observed upon loss of ZNF326. We observed that the alternatively spliced transcripts of a subset of these genes, involved in proliferation and tumor cell migration like REPIN1/AP4, ST3GAL6, TRNAU1AP and PFKM are degraded upon loss of PRMT5. In summary, we have identified a novel mechanism through which the PRMT5/WDR77 complex maintains the balance between splicing and mRNA stability through methylation of ZNF326.

Place, publisher, year, edition, pages
Oxford University Press, 2017
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-142249 (URN)10.1093/nar/gkx727 (DOI)000414552300019 ()28977470 (PubMedID)
Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2018-11-27Bibliographically approved
Aguilo, F., Li, S., Balasubramaniyan, N., Sancho, A., Benko, S., Zhang, F., . . . Walsh, M. J. (2016). Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α. Cell reports, 14(3), 479-492
Open this publication in new window or tab >>Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 479-492Article in journal (Refereed) Published
Abstract [en]

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-129269 (URN)10.1016/j.celrep.2015.12.043 (DOI)000368701600010 ()26774474 (PubMedID)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-11-27Bibliographically approved
Aguilo, F., Di Cecilia, S. & Walsh, M. J. (2016). Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease. In: Long non-coding RNAs in human disease: (pp. 29-39). Springer, 394
Open this publication in new window or tab >>Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease
2016 (English)In: Long non-coding RNAs in human disease, Springer, 2016, Vol. 394, p. 29-39Chapter in book (Refereed)
Abstract [en]

The long non-coding RNA CDKN2B-AS1, commonly referred to as the Antisense Non-coding RNA in the INK4 Locus (ANRIL), is a 3.8-kb-long RNA transcribed from the short arm of human chromosome 9 on p21.3 that overlaps a critical region encompassing three major tumor suppressor loci juxtaposed to the INK4b-ARF-INK4a gene cluster and the methyl-thioadenosine phosphorylase (MTAP) gene. Genome-wide association studies have identified this region with a remarkable and growing number of disease-associated DNA alterations and single nucleotide polymorphisms, which corresponds to increased susceptibility to human disease. Recent attention has been devoted on whether these alterations in the ANRIL sequence affect its expression levels and/or its splicing transcript variation, and in consequence, global cellular homeostasis. Moreover, recent evidence postulates that ANRIL not only can regulate their immediate genomic neighbors in cis, but also has the capacity to regulate additional loci in trans. This action would further increase the complexity for mechanisms imposed through ANRIL and furthering the scope of this lncRNA in disease pathogenesis. In this chapter, we summarize the most recent findings on the investigation of ANRIL and provide a perspective on the biological and clinical significance of ANRIL as a putative biomarker, specifically, its potential role in directing cellular fates leading to cancer and cardiovascular disease.

Place, publisher, year, edition, pages
Springer, 2016
Series
Current Topics in Microbiology and Immunology, ISSN 0070-217X ; 394
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-129268 (URN)10.1007/82_2015_455 (DOI)000385417100003 ()26220772 (PubMedID)978-3-319-23906-4 (ISBN)978-3-319-23907-1 (ISBN)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2019-05-10Bibliographically approved
Di Cecilia, S., Zhang, F., Sancho, A., Li, S., Aguiló, F., Sun, Y., . . . Walsh, M. J. (2016). RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells. Cancer Research, 76(19), 5615-5627
Open this publication in new window or tab >>RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells
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2016 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 19, p. 5615-5627Article in journal (Refereed) Published
Abstract [en]

Cancer-initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC Accumulating evidence indicates that long noncoding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC. Its silencing impaired WNT signaling, whereas its overexpression enforced WNT signaling, cell growth, and survival in serum-free media. RBM5-AS1 has been little characterized previously, and we determined it to be a nuclear-retained transcript that selectively interacted with β-catenin. Mechanistic investigations showed that silencing or overexpression of RBM5-AS1 caused a respective loss or retention of β-catenin from TCF4 complexes bound to the WNT target genes SGK1, YAP1, and MYC Our work suggests that RBM5-AS1 activity is critical for the functional enablement of colon cancer stem-like cells. Furthermore, it defines the mechanism of action of RBM5-AS1 in the WNT pathway via physical interactions with β-catenin, helping organize transcriptional complexes that sustain colon CIC function. 

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-129272 (URN)10.1158/0008-5472.CAN-15-1824 (DOI)000385625500008 ()27520449 (PubMedID)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-11-27Bibliographically approved
Ren, C., Smith, S. G., Yap, K., Li, S., Li, J., Mezei, M., . . . Zhou, M.-M. (2016). Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7 [Letter to the editor]. ACS Medicinal Chemistry Letters, 7(6), 601-605
Open this publication in new window or tab >>Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7
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2016 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 6, p. 601-605Article in journal, Letter (Refereed) Published
Abstract [en]

The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a) in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.

Keywords
Chromodomain, polycomb repressive complex, antagonist, gene transcription
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-129270 (URN)10.1021/acsmedchemlett.6b00042 (DOI)000377845200013 ()27326334 (PubMedID)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-11-27Bibliographically approved
Lee, D.-F., Walsh, M. J. & Aguiló, F. (2016). ZNF217/ZFP217 Meets Chromatin and RNA. TIBS -Trends in Biochemical Sciences. Regular ed., 41(12), 986-988
Open this publication in new window or tab >>ZNF217/ZFP217 Meets Chromatin and RNA
2016 (English)In: TIBS -Trends in Biochemical Sciences. Regular ed., ISSN 0968-0004, E-ISSN 1362-4326, Vol. 41, no 12, p. 986-988Article in journal, Editorial material (Refereed) Published
Abstract [en]

The Kruppel-like transcription factor zinc finger protein (ZNF)217 (mouse homolog ZFP217) contributes to tumorigenesis by dysregulating gene expression programs. The newly discovered molecular function of ZFP217 in controlling N6-methyladenosine (m6A) deposition in embryonic stem cells (ESCs) sheds new light on the role of this transcription factor in tumor development.

Keywords
ZNF217, cancer, stem cell, N6-methyladenosine, RNA methylation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-129271 (URN)10.1016/j.tibs.2016.07.013 (DOI)000389106400003 ()27519282 (PubMedID)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-06-09Bibliographically approved
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