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  • 1.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long non-coding RNA and Polycomb: an intricate partnership in cancer biology2018In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 23, p. 2106-2132Article in journal (Refereed)
    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).

  • 2.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long Noncoding RNAs as Players in Breast Tumorigenesis2020In: The chemical biology of long noncoding RNAs / [ed] Stefan Jurga, Jan Barciszewski, Springer, 2020, , p. 19p. 385-403Chapter in book (Refereed)
    Abstract [en]

    Comprehensive analysis of the mammalian genome uncovered the discovery of pervasive transcription of large RNA transcripts that do not code for proteins, namely, long noncoding RNAs (lncRNAs). LncRNAs play important roles in the regulation of gene expression from integration of chromatin remodeling complexes to transcriptional and posttranscriptional regulation of protein-coding genes. Application of next-generation sequencing technologies to cancer transcriptomes has revealed that aberrant expression of lncRNAs is associated with tumor progression and metastasis. Although thousands of lncRNAs have been shown to be dysregulated in different cancer types, just few of them have been fully characterized. In this book chapter, we aim to highlight recent findings of the mechanistic function of lncRNAs in breast cancer and summarize key examples of lncRNAs that are misregulated during breast tumorigenesis. We have categorized breast cancer–associated lncRNA according to their contribution to tumor suppression or tumor progression based on recent studies. Because some of them are expressed in a specific molecular breast cancer subtype, we have outlined lncRNAs that can potentially serve as diagnostic and prognostic markers, in which expression is linked to chemotherapy resistance. Finally, we have discussed current limitations and perspectives on potential lncRNA targets for use in therapies against breast cancer.

  • 3.
    Achour, Cyrinne
    et al.
    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).
    Bhattarai, Devi Prasad
    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).
    Groza, Paula
    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).
    Roman, Ángel-Carlos
    Department of Molecular Biology and Genetics, University of Extremadura, Badajoz, Spain.
    Aguilo, Francesca
    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).
    METTL3 regulates breast cancer-associated alternative splicing switches2023In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 42, p. 911-925Article in journal (Refereed)
    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.

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  • 4. Aguilo, Francesca
    et al.
    Avagyan, Serine
    Labar, Amy
    Sevilla, Ana
    Lee, Dung-Fang
    Kumar, Parameet
    Lemischka, Ihor R
    Zhou, Betty Y
    Snoeck, Hans-Willem
    Prdm16 is a physiologic regulator of hematopoietic stem cells.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 19Article in journal (Refereed)
    Abstract [en]

    Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

  • 5.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Di Cecilia, Serena
    Walsh, Martin J
    Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease2016In: 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.

  • 6.
    Aguilo, Francesca
    et al.
    Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Li, SiDe
    Balasubramaniyan, Natarajan
    Sancho, Ana
    Benko, Sabina
    Zhang, Fan
    Vashisht, Ajay
    Rengasamy, Madhumitha
    Andino, Blanca
    Chen, Chih-hung
    Zhou, Felix
    Qian, Chengmin
    Zhou, Ming-Ming
    Wohlschlegel, James A
    Zhang, Weijia
    Suchy, Frederick J
    Walsh, Martin J
    Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 3, p. 479-492Article in journal (Refereed)
    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.

  • 7.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Walsh, Martin J.
    The N6-Methyladenosine RNA modification in pluripotency and reprogramming2017In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed)
    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.

  • 8.
    Aguilo, Francesca
    et al.
    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Zakirova, Zuchra
    Nolan, Katie
    Wagner, Ryan
    Sharma, Rajal
    Hogan, Megan
    Wei, Chengguo
    Sun, Yifei
    Walsh, Martin J.
    Kelley, Kevin
    Zhang, Weijia
    Ozelius, Laurie J.
    Gonzalez-Alegre, Pedro
    Zwaka, Thomas P.
    Ehrlich, Michelle E.
    THAP1: role in mouse embryonic stem cell survival and differentiation2017In: Stem Cell Reports, ISSN 2213-6711, Vol. 9, no 1, p. 92-107Article in journal (Refereed)
    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.

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  • 9. Aguilo, Francesca
    et al.
    Zhang, Fan
    Sancho, Ana
    Fidalgo, Miguel
    Di Cecilia, Serena
    Vashisht, Ajay
    Lee, Dung-Fang
    Chen, Chih-Hung
    Rengasamy, Madhumitha
    Andino, Blanca
    Jahouh, Farid
    Roman, Angel
    Krig, Sheryl R
    Wang, Rong
    Zhang, Weijia
    Wohlschlegel, James A
    Wang, Jianlong
    Walsh, Martin J
    Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.2015In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 17, no 6, p. 689-704Article in journal (Refereed)
    Abstract [en]

    Epigenetic and epitranscriptomic networks have important functions in maintaining the pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However, the mechanisms integrating the actions of these distinct networks are only partially understood. Here we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates the transcription of key pluripotency genes, and modulates N6-methyladenosine (m(6)A) deposition on their transcripts by sequestering the enzyme m(6)A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m(6)A RNA levels, and enhances m(6)A modification of the Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3 associated, and is enriched at promoters of m(6)A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m(6)A RNA modification to ensure ESC identity.

  • 10. Aguilo, Francesca
    et al.
    Zhou, Ming-Ming
    Walsh, Martin J
    Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 16Article in journal (Refereed)
    Abstract [en]

    Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF-INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF-INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b-ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development.

  • 11. Aguiló, Francesca
    et al.
    Camarero, Nuria
    Relat, Joana
    Marrero, Pedro F
    Haro, Diego
    Transcriptional regulation of the human acetoacetyl-CoA synthetase gene by PPARgamma.2010In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 427, no 2Article in journal (Refereed)
    Abstract [en]

    In the cytosol of lipogenic tissue, ketone bodies are activated by AACS (acetoacetyl-CoA synthetase) and incorporated into cholesterol and fatty acids. AACS gene expression is particularly abundant in white adipose tissue, as it is induced during adipocyte differentiation. In order to elucidate the mechanism controlling the gene expression of human AACS and to clarify its physiological role, we isolated the human promoter, characterized the elements required to initiate transcription and analysed the expression of the gene in response to PPARgamma (peroxisome-proliferator-activated receptor gamma), an inducer of adipogenesis. We show that the human AACS promoter is a PPARgamma target gene and that this nuclear receptor is recruited to the AACS promoter by direct interaction with Sp1 (stimulating protein-1).

  • 12. Avagyan, Serine
    et al.
    Aguilo, Francesca
    Kamezaki, Kenjiro
    Snoeck, Hans-Willem
    Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 23Article in journal (Refereed)
    Abstract [en]

    Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

  • 13.
    Bhattarai, Devi Prasad
    et al.
    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).
    Aguilo, Francesca
    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).
    m6A RNA immunoprecipitation followed by high-throughput sequencing to map N6-Methyladenosine2022In: 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.

  • 14.
    Boccaletto, Pietro
    et al.
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Stefaniak, Filip
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Ray, Angana
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Cappannini, Andrea
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Mukherjee, Sunandan
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Purta, Elżbieta
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Kurkowska, Małgorzata
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Shirvanizadeh, Niloofar
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    Destefanis, Eliana
    Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
    Groza, Paula
    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).
    Avşar, Gülben
    Department of Bioengineering, Gebze Technical University, Kocaeli, Turkey.
    Romitelli, Antonia
    Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, Firenze, Italy; Department of Medical Biotechnologies, Università di Siena.
    Pir, Pınar
    Department of Bioengineering, Gebze Technical University, Kocaeli, Turkey.
    Dassi, Erik
    Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
    Conticello, Silvestro G.
    Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, Firenze, Italy; Institute of Clinical Physiology, National Research Council, Pisa, Italy.
    Aguilo, Francesca
    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).
    Bujnicki, Janusz M.
    Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
    MODOMICS: a database of RNA modification pathways. 2021 update2022In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no D1, p. D231-D235Article in journal (Refereed)
    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/.

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  • 15.
    Destefanis, Eliana
    et al.
    Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy; The Epitran Cost Action Consortium, COST Action CA16120.
    Avşar, Gülben
    The Epitran Cost Action Consortium, COST Action CA16120; Department of Bioengineering, Gebze Technical University, Kocaeli, Turkey.
    Groza, Paula
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). The Epitran Cost Action Consortium, COST Action CA16120.
    Romitelli, Antonia
    The Epitran Cost Action Consortium, COST Action CA16120; Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, Firenze, Italy; Department of Medical Biotechnologies, Università di Siena, Siena, Italy.
    Torrini, Serena
    The Epitran Cost Action Consortium, COST Action CA16120; Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, Firenze, Italy; Department of Medical Biotechnologies, Università di Siena, Siena, Italy.
    Pir, Pinar
    The Epitran Cost Action Consortium, COST Action CA16120; Department of Bioengineering, Gebze Technical University, Kocaeli, Turkey.
    Conticello, Silvestro G.
    The Epitran Cost Action Consortium, COST Action CA16120; Core Research Laboratory, ISPRO-Institute for Cancer Research, Prevention and Clinical Network, Firenze, Italy; Institute of Clinical Physiology, National Research Council, Pisa, Italy.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). The Epitran Cost Action Consortium, COST Action CA16120.
    Dassi, Erik
    Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy; The Epitran Cost Action Consortium, COST Action CA16120.
    A mark of disease: How mRNA modifications shape genetic and acquired pathologies2021In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 27, no 4, p. 367-389Article, review/survey (Refereed)
    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.

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  • 16. Di Cecilia, Serena
    et al.
    Zhang, Fan
    Sancho, Ana
    Li, SiDe
    Aguiló, Francesca
    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York.
    Sun, Yifei
    Rengasamy, Madhumitha
    Zhang, Weijia
    Del Vecchio, Luigi
    Salvatore, Francesco
    Walsh, Martin J.
    RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 19, p. 5615-5627Article in journal (Refereed)
    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. 

  • 17.
    Kumari, Kanchan
    et al.
    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).
    Groza, Paula
    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).
    Aguilo, Francesca
    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).
    Regulatory roles of RNA modifications in breast cancer2021In: NAR Cancer, E-ISSN 2632-8674, Vol. 3, no 3, article id zcab036Article, review/survey (Refereed)
    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.

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  • 18. Lee, Dung-Fang
    et al.
    Su, Jie
    Ang, Yen-Sin
    Carvajal-Vergara, Xonia
    Mulero-Navarro, Sonia
    Pereira, Carlos F
    Gingold, Julian
    Wang, Hung-Liang
    Zhao, Ruiying
    Sevilla, Ana
    Darr, Henia
    Williamson, Andrew J K
    Chang, Betty
    Niu, Xiaohong
    Aguilo, Francesca
    Flores, Elsa R
    Sher, Yuh-Pyng
    Hung, Mien-Chie
    Whetton, Anthony D
    Gelb, Bruce D
    Moore, Kateri A
    Snoeck, Hans-Willem
    Ma'ayan, Avi
    Schaniel, Christoph
    Lemischka, Ihor R
    Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling.2012In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 11, no 2Article in journal (Refereed)
    Abstract [en]

    Many signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming.

  • 19. Lee, Dung-Fang
    et al.
    Walsh, Martin J.
    Aguiló, Francesca
    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
    ZNF217/ZFP217 Meets Chromatin and RNA2016In: Trends in Biochemical Sciences (TIBS), ISSN 0968-0004, E-ISSN 1362-4326, Vol. 41, no 12, p. 986-988Article in journal (Refereed)
    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.

  • 20.
    Malla, Sandhya
    et al.
    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).
    Bhattarai, Devi Prasad
    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).
    Groza, Paula
    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).
    Melguizo-Sanchis, Dario
    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).
    Atanasoai, Ionut
    Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
    Martinez Gamero, Carlos
    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).
    Román, Ángel-Carlos
    Department of Biochemistry, Molecular Biology and Genetics, University of Extremadura, Badajoz, Spain.
    Zhu, Dandan
    Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, TX, Houston, United States.
    Lee, Dung-Fang
    Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, TX, Houston, United States; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, TX, Houston, United States; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, TX, Houston, United States; Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, TX, Houston, United States.
    Kutter, Claudia
    Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
    Aguilo, Francesca
    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).
    ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export2022In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 23, no 3, article id e53191Article in journal (Refereed)
    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.

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  • 21.
    Malla, Sandhya
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Kumari, Kanchan
    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).
    Martinez Gamero, Carlos
    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).
    Achour, Cyrinne
    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).
    Mermelekas, Georgios
    Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 21, Solna, Sweden.
    Coege, Alba
    Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela (USC)-Health Research Institute (IDIS), Santiago de Compostela, Spain.
    Guallar, Diana
    Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela (USC)-Health Research Institute (IDIS), Santiago de Compostela, Spain; Department of Biochemistry and Molecular Biology, USC, Santiago de Compostela, Spain.
    Roman, Angel
    Department of Biochemistry, Molecular Biology and Genetics, University of Extremadura, Badajoz, Spain.
    Aguilo, Francesca
    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).
    LSD1 interacts with CHD7 to regulate the chromatin landscape in mouse embryonic stem cellsManuscript (preprint) (Other academic)
    Abstract [en]

     

     

     

  • 22.
    Malla, Sandhya
    et al.
    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).
    Kumari, Kanchan
    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).
    Martinez Gamero, Carlos
    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).
    García-Prieto, carlos A.
    Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain .
    Álvarez-Errico3, Damiana
    Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain .
    Stransky, Stephanie
    4Department of Biochemistry, Albert Einstein College of Medicine, 10461 Bronx, NY, USA.
    Caroli, Jonatan
    5Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
    Saiki, Paulina Avovome
    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).
    Lai, Weiyi
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Lyu, Cong
    6State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Mattevi, Andrea
    Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wang, Hailin
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
    Sidoli, Simone
    4Department of Biochemistry, Albert Einstein College of Medicine, 10461 Bronx, NY, USA.
    Esteller, Manel
    Centro de Investigacion Biomedica en Red Cancer (CIBERONC, 28029 Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain.
    Roman, Angel
    Department of Biochemistry, Molecular Biology and Genetics, University of Extremadura, Badajoz, 06071, Spain.
    Aguilo, Francesca
    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).
    The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cellsManuscript (preprint) (Other academic)
  • 23.
    Malla, Sandhya
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Melguizo-Sanchis, Dario
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steering pluripotency and differentiation with N6-methyladenosine RNA modification2019In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, no 3, p. 394-402Article in journal (Refereed)
    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.

  • 24. Martin, Nadine
    et al.
    Popov, Nikolay
    Aguilo, Francesca
    O'Loghlen, Ana
    Raguz, Selina
    Snijders, Ambrosius P
    Dharmalingam, Gopuraja
    Li, Side
    Thymiakou, Efstathia
    Carroll, Thomas
    Zeisig, Bernd B
    So, Chi Wai Eric
    Peters, Gordon
    Episkopou, Vasso
    Walsh, Martin J
    Gil, Jesús
    Interplay between Homeobox proteins and Polycomb repressive complexes in p16INK⁴a regulation.2013In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 32, no 7Article in journal (Refereed)
    Abstract [en]

    The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

  • 25.
    Martinez-Gamero, Carlos
    et al.
    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).
    Malla, Sandhya
    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).
    Aguilo, Francesca
    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).
    LSD1: Expanding functions in stem cells and differentiation2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3252Article, review/survey (Refereed)
    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.

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  • 26.
    Relier, Sébastien
    et al.
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    Ripoll, Julie
    LIRMM, Univ. Montpellier, CNRS, Montpellier, France.
    Guillorit, Hélène
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France; Stellate Therapeutics, Paris, France.
    Amalric, Amandine
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    Achour, Cyrinne
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Boissière, Florence
    ICM, Montpellier, France.
    Vialaret, Jérôme
    IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France; INM, Univ. Montpellier, INSERM, Montpellier, France.
    Attina, Aurore
    IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France; INM, Univ. Montpellier, INSERM, Montpellier, France.
    Debart, Françoise
    IBMM, CNRS, Univ. Montpellier, ENSCM, Montpellier, France.
    Choquet, Armelle
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    Macari, Françoise
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    Marchand, Virginie
    Université de Lorraine, IMoPA UMR7365 CNRS-UL and UMS2008/US40 IBSLor, UL-CNRS-INSERM, BioPole, Vandoeuvre-les-Nancy, France.
    Motorin, Yuri
    Université de Lorraine, IMoPA UMR7365 CNRS-UL and UMS2008/US40 IBSLor, UL-CNRS-INSERM, BioPole, Vandoeuvre-les-Nancy, France.
    Samalin, Emmanuelle
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France; ICM, Montpellier, France.
    Vasseur, Jean-Jacques
    IBMM, CNRS, Univ. Montpellier, ENSCM, Montpellier, France.
    Pannequin, Julie
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lopez-Crapez, Evelyne
    ICM, Montpellier, France.
    Hirtz, Christophe
    IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France; INM, Univ. Montpellier, INSERM, Montpellier, France.
    Rivals, Eric
    LIRMM, Univ. Montpellier, CNRS, Montpellier, France.
    Bastide, Amandine
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
    David, Alexandre
    IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France; IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France.
    FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 1716Article in journal (Refereed)
    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.

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  • 27. Ren, Chunyan
    et al.
    Smith, Steven G.
    Yap, Kyoko
    Li, SiDe
    Li, Jiaojie
    Mezei, Mihaly
    Rodriguez, Yoel
    Vincek, Adam
    Aguilo, Francesca
    Department of Structural and Chemical Biology and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
    Walsh, Martin J.
    Zhou, Ming-Ming
    Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX72016In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 7, no 6, p. 601-605Article in journal (Refereed)
    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.

  • 28. Rengasamy, Madhumitha
    et al.
    Zhang, Fan
    Vashisht, Ajay
    Song, Won-Min
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sun, Yifei
    Li, SiDe
    Zhang, Weijia
    Zhang, Bin
    Wohlschlegel, James A.
    Walsh, Martin J.
    The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 19, p. 11106-11120Article in journal (Refereed)
    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.

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  • 29. Sancho, Ana
    et al.
    Li, SiDe
    Paul, Thankam
    Zhang, Fan
    Aguilo, Francesca
    Vashisht, Ajay
    Balasubramaniyan, Natarajan
    Leleiko, Neal S
    Suchy, Frederick J
    Wohlschlegel, James A
    Zhang, Weijia
    Walsh, Martin J
    CHD6 regulates the topological arrangement of the CFTR locus2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 10, p. 2724-2732Article in journal (Refereed)
    Abstract [en]

    The control of transcription is regulated through the well-coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome-wide and topological organization of distal intra-chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types. Here, we identified CHD6 from a screen among several chromatin-remodeling proteins as a putative epigenetic modulator of CFTR expression. Moreover, our findings of CTCF interactions with CHD6 are consistent with the role described previously for CTCF in CFTR regulation. Our results now reveal that the CHD6 protein lies within the infrastructure of multiple transcriptional complexes, such as the FACT, PBAF, PAF1C, Mediator, SMC/Cohesion and MLL complexes. This model underlies the fundamental role CHD6 facilitates by tethering cis-acting regulatory elements of CFTR in proximity to these multi-subunit transcriptional protein complexes. Finally, we indicate that CHD6 structurally coordinates a three-dimensional stricture between intragenic elements of CFTR bound by several cell-type specific transcription factors, such as CDX2, SOX18, HNF4α and HNF1α. Therefore, our results reveal new insights into the epigenetic regulation of CFTR expression, whereas the manipulation of CFTR gene topology could be considered for treating specific indications of cystic fibrosis and/or pancreatitis.

  • 30.
    Xu, An
    et al.
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Liu, Mo
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Huang, Mo-Fan
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States.
    Zhang, Yang
    College of Science, Harbin Institute of Technology (Shenzhen), Guangdong, Shenzhen, China.
    Hu, Ruifeng
    Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Gingold, Julian A.
    Department of Obstetrics & Gynecology and Women's Health, Einstein/Montefiore Medical Center, NY, Bronx, United States.
    Liu, Ying
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Zhu, Dandan
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Chien, Chian-Shiu
    Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
    Wang, Wei-Chen
    Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
    Liao, Zian
    Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States.
    Yuan, Fei
    Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States.
    Hsu, Chih-Wei
    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, TX, Houston, United States.
    Tu, Jian
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Yu, Yao
    Department of Epidemiology, University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Rosen, Taylor
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Xiong, Feng
    Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Jia, Peilin
    Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Yang, Yi-Ping
    Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
    Bazer, Danielle A.
    Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States.
    Chen, Ya-Wen
    Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
    Li, Wenbo
    University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Huff, Chad D.
    University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Department of Epidemiology, University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Zhu, Jay-Jiguang
    Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Aguilo, Francesca
    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).
    Chiou, Shih-Hwa
    Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
    Boles, Nathan C.
    Neural Stem Cell Institute, NY, Rensselaer, United States.
    Lai, Chien-Chen
    Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan; Graduate institute of Chinese Medical Science, China Medical University, Taichung, Taiwan; Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
    Hung, Mien-Chie
    Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, Office of the President, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan.
    Zhao, Zhongming
    University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Van Nostrand, Eric L.
    Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States.
    Zhao, Ruiying
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Lee, Dung-Fang
    Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States; Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, TX, Houston, United States.
    Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 1694Article in journal (Refereed)
    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.

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