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1,186 results on '"Fraga, Mario"'

1. A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Author

Pérez, Raúl F., Tezanos, Patricia, Peñarroya, Alfonso, González-Ramón, Alejandro, Urdinguio, Rocío G., Gancedo-Verdejo, Javier, Tejedor, Juan Ramón, Santamarina-Ojeda, Pablo, Alba-Linares, Juan José, Sainz-Ledo, Lidia, Roberti, Annalisa, López, Virginia, Mangas, Cristina, Moro, María, Cintado Reyes, Elisa, Muela Martínez, Pablo, Rodríguez-Santamaría, Mar, Ortea, Ignacio, Iglesias-Rey, Ramón, Castilla-Silgado, Juan, Tomás-Zapico, Cristina, Iglesias-Gutiérrez, Eduardo, Fernández-García, Benjamín, Sanchez-Mut, Jose Vicente, Trejo, José Luis, Fernández, Agustín F., and Fraga, Mario F.

Published
2024
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3. The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma

Author

Morgado-Palacin, Lucia, Brown, Jessie A, Martinez, Thomas F, Garcia-Pedrero, Juana M, Forouhar, Farhad, Quinn, S Aidan, Reglero, Clara, Vaughan, Joan, Heydary, Yasamin Hajy, Donaldson, Cynthia, Rodriguez-Perales, Sandra, Allonca, Eva, Granda-Diaz, Rocio, Fernandez, Agustin F, Fraga, Mario F, Kim, Arianna L, Santos-Juanes, Jorge, Owens, David M, Rodrigo, Juan P, Saghatelian, Alan, and Ferrando, Adolfo A

Subjects
Genetics, Stem Cell Research, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Mice, Humans, Ubiquitin, Carcinoma, Squamous Cell, Genes, Tumor Suppressor, Keratinocytes, Head and Neck Neoplasms, RNA, Long Noncoding, Cell Line, Tumor, Gene Expression Regulation, Neoplastic
Abstract

The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.

Published
2023

4. NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression

Author

Lopez-Millan, Belén, Rubio-Gayarre, Alba, Vinyoles, Meritxell, Trincado, Juan L., Fraga, Mario F., Fernandez-Fuentes, Narcís, Guerrero-Murillo, Mercedes, Martinez, Alba, Velasco-Hernandez, Talia, Falgàs, Aïda, Panisello, Carla, Valcarcel, Gemma, Sardina, José Luis, López-Martí, Paula, Javierre, Biola M., Del Valle-Pérez, Beatriz, García de Herreros, Antonio, Locatelli, Franco, Pieters, Rob, Bardini, Michela, Cazzaniga, Giovanni, Rodríguez-Manzaneque, Juan Carlos, Hanewald, Thomas, Marschalek, Rolf, Milne, Thomas A., Stam, Ronald W., Tejedor, Juan Ramón, Menendez, Pablo, and Bueno, Clara

Published
2024
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5. The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis

Author

Mercado-Gómez, Maria, Goikoetxea-Usandizaga, Naroa, Kerbert, Annarein J.C., Gracianteparaluceta, Leire Uraga, Serrano-Maciá, Marina, Lachiondo-Ortega, Sofia, Rodriguez-Agudo, Rubén, Gil-Pitarch, Clàudia, Simón, Jorge, González-Recio, Irene, Fondevila, Marcos F., Santamarina-Ojeda, Pablo, Fraga, Mario F., Nogueiras, Rubén, Heras, Javier de las, Jalan, Rajiv, Martínez-Chantar, María Luz, and Delgado, Teresa C.

Published
2024
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6. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma

Author

Rey, Verónica, Tornín, Juan, Alba-Linares, Juan Jose, Robledo, Cristina, Murillo, Dzohara, Rodríguez, Aida, Gallego, Borja, Huergo, Carmen, Viera, Cristina, Braña, Alejandro, Astudillo, Aurora, Heymann, Dominique, Szuhai, Karoly, Bovée, Judith V.M.G., Fernández, Agustín F., Fraga, Mario F., Alonso, Javier, and Rodríguez, René

Published
2024
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8. CRISPR/dCAS9-mediated DNA demethylation screen identifies functional epigenetic determinants of colorectal cancer

Author

Tejedor, Juan Ramón, Peñarroya, Alfonso, Gancedo-Verdejo, Javier, Santamarina-Ojeda, Pablo, Pérez, Raúl F., López-Tamargo, Sara, Díez-Borge, Ana, Alba-Linares, Juan J., González-del-Rey, Nerea, Urdinguio, Rocío G., Mangas, Cristina, Roberti, Annalisa, López, Virginia, Morales-Ruiz, Teresa, Ariza, Rafael R., Roldán-Arjona, Teresa, Meijón, Mónica, Valledor, Luis, Cañal, María Jesús, Fernández-Martínez, Daniel, Fernández-Hevia, María, Jiménez-Fonseca, Paula, García-Flórez, Luis J., Fernández, Agustín F., and Fraga, Mario F.

Published
2023
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12. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype

Author

Cuesta-Borràs, Estefania, Salvans, Cándida, Arqués, Oriol, Chicote, Irene, Ramírez, Lorena, Cabellos, Laia, Martínez-Quintanilla, Jordi, Mur-Espinosa, Alex, García-Álvarez, Alejandro, Hernando, Jorge, Tejedor, Juan Ramón, Mirallas, Oriol, Élez, Elena, Fraga, Mario F., Tabernero, Josep, Nuciforo, Paolo, Capdevila, Jaume, Palmer, Héctor G., and Puig, Isabel

Published
2023
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16. MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis.

Author

Fernández-Ramos, David, Fernández-Tussy, Pablo, Lopitz-Otsoa, Fernando, Gutiérrez-de-Juan, Virginia, Navasa, Nicolás, Barbier-Torres, Lucía, Zubiete-Franco, Imanol, Simón, Jorge, Fernández, Agustín F, Arbelaiz, Ander, Aransay, Ana M, Lavín, José Luis, Beraza, Naiara, Perugorria, María J, Banales, Jesus M, Villa, Erica, Fraga, Mario F, Anguita, Juan, Avila, Matias A, Berasain, Carmen, Iruzibieta, Paula, Crespo, Javier, Lu, Shelly C, Varela-Rey, Marta, Mato, José M, Delgado, Teresa C, and Martínez-Chantar, María L

Subjects
Liver, Animals, Mice, Inbred C57BL, Humans, Mice, Carcinoma, Hepatocellular, Liver Cirrhosis, Fibrosis, MicroRNAs, Cell Proliferation, Male, Glycine N-Methyltransferase, Hepatic Stellate Cells, Inbred C57BL, Carcinoma, Hepatocellular, Biochemistry and Cell Biology, Oncology and Carcinogenesis
Abstract

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3'UTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.

Published
2018

17. PCDHGC3 hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas

Author

Cubiella, Tamara, primary, Celada, Lucía, additional, San‐Juan‐Guardado, Jaime, additional, Rodríguez‐Aguilar, Raúl, additional, Suárez‐Priede, Álvaro, additional, Poch, María, additional, Dominguez, Francisco, additional, Fernández‐Vega, Iván, additional, Montero‐Pavón, Pedro, additional, Fraga, Mario F, additional, Nakatani, Yoichiro, additional, Takata, So, additional, Yachida, Shinichi, additional, Valdés, Nuria, additional, and Chiara, María‐Dolores, additional

Published
2024
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18. Physical exercise shapes the mouse brain epigenome

Author

Urdinguio, Rocío G., Tejedor, Juan Ramon, Fernández-Sanjurjo, Manuel, Pérez, Raúl F., Peñarroya, Alfonso, Ferrero, Cecilia, Codina-Martínez, Helena, Díez-Planelles, Carlos, Pinto-Hernández, Paola, Castilla-Silgado, Juan, Coto-Vilcapoma, Almudena, Díez-Robles, Sergio, Blanco-Agudín, Noelia, Tomás-Zapico, Cristina, Iglesias-Gutiérrez, Eduardo, Fernández-García, Benjamín, Fernandez, Agustin F., and Fraga, Mario F.

Published
2021
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20. Epigenetic loss of m1A RNA demethylase ALKBH3 in Hodgkin lymphoma targets collagen, conferring poor clinical outcome

Author

Esteve-Puig, Rosaura, Climent, Fina, Piñeyro, David, Domingo-Domènech, Eva, Davalos, Veronica, Encuentra, Maite, Rea, Anna, Espejo-Herrera, Nadia, Soler, Marta, Lopez, Miguel, Ortiz-Barahona, Vanessa, Tapia, Gustavo, Navarro, José-Tomás, Cid, Joan, Farré, Lourdes, Villanueva, Alberto, Casanova, Isolda, Mangues, Ramon, Santamarina-Ojeda, Pablo, Fernández, Agustín F., Fraga, Mario F., Piris, Miguel Angel, Kol, Nitzan, Avrahami, Chen, Moshitch-Moshkovitz, Sharon, Rechavi, Gideon, Sureda, Anna, and Esteller, Manel

Published
2021
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21. Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation

Author

Caja Rural de Asturias, Sociedad Asturiana de Diabetes, Endocrinología, Nutrición y Obesidad, Universidad de Barcelona, Villa-Fernández, Elsa, Garcia, Ana Victoria, Fernández-Fernández, Alejandra, García-Villarino, Miguel, Ares-Blanco, Jessica, Pujante Alarcón, Pedro, González-Vidal, Tomás, Fraga, Mario F., Menéndez Torre, Edelmiro, Delgado-Álvarez, Elías, Lambert, Carmen, Caja Rural de Asturias, Sociedad Asturiana de Diabetes, Endocrinología, Nutrición y Obesidad, Universidad de Barcelona, Villa-Fernández, Elsa, Garcia, Ana Victoria, Fernández-Fernández, Alejandra, García-Villarino, Miguel, Ares-Blanco, Jessica, Pujante Alarcón, Pedro, González-Vidal, Tomás, Fraga, Mario F., Menéndez Torre, Edelmiro, Delgado-Álvarez, Elías, and Lambert, Carmen

Abstract

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin’s are being analysed.

Published
2024

22. A FokI-driven signal amplification platform for the simultaneous detection of multiple viral RNA pathogens

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Principado de Asturias, Tejedor, Juan Ramón, Roberti, Annalisa, Mangas, Cristina, Álvarez-Argüelles, Marta E., Rojo-Alba, Susana, Boga, José A., Fernández, Agustín F., Melón, Santiago, Rodríguez, Mercedes, Fraga, Mario F., European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Principado de Asturias, Tejedor, Juan Ramón, Roberti, Annalisa, Mangas, Cristina, Álvarez-Argüelles, Marta E., Rojo-Alba, Susana, Boga, José A., Fernández, Agustín F., Melón, Santiago, Rodríguez, Mercedes, and Fraga, Mario F.

Abstract

Accurate signal quantification is a critical parameter for precise pathogen diagnosis. Furthermore, the development of novel diagnostic methods amenable for portable or scalable purposes may facilitate the real-time surveillance of emerging pathogenic threats. Here, we extrapolated the use of a FokI-driven signal amplification approach, powered by the nickase activity of the FokI restriction endonuclease, to enhance the signal detection of multiple respiratory viral pathogens relevant to human health. This approach utilises a set of dumbbell-like fluorescent oligonucleotides against three families of human single-stranded RNA respiratory viruses (Coronaviridae, Paramyxoviridae, and Pneumoviridae), including human betacoronaviruses (OC43/HKU1), human betacoronavirus SARS-CoV-2, human parainfluenza viruses (HPIV1/HPIV3/HPIV2/HPIV4), and human metapneumovirus (HMPV)/respiratory syncytial virus (HRSV). FokI-assisted digestion of these dumbbell-like fluorescent probes in the presence of their respective viral targets enhanced their detectable signal in a highly specific manner. In addition, this technique exhibited high multiplex potential to detect multiple viral targets in a single assay. A molecular coupling between the FokI-assisted reaction and the isothermal rolling circle amplification technique significantly improved the limit of detection in samples from infected patients, ensuring adequate specificity and sensitivity. These results highlight the diagnostic potential of this methodology, representing a cost-effective alternative for the identification of respiratory viral pathogens of interest to the public healthcare system.

Published
2024

25. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications

Author

Bock, Christoph, Halbritter, Florian, Carmona, Francisco J, Tierling, Sascha, Datlinger, Paul, Assenov, Yassen, Berdasco, Maria, Bergmann, Anke K, Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M, Diep, Dinh, Fernandez, Agustin F, Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Klaever, Ruth, Kreutz, Martin, Kulis, Marta, Lopez, Virginia, Nair, Shalima S, Paul, Dirk S, Plongthongkum, Nongluk, Qu, Wenjia, Queiros, Ana C, Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocio G, Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J, Beck, Stephan, Clark, Susan J, Esteller, Manel, Ferguson-Smith, Anne C, Fraga, Mario F, Guldberg, Per, Hansen, Lise Lotte, Laird, Peter W, Martin-Subero, Jose I, Nygren, Anders OH, Peist, Ralf, Plass, Christoph, Shames, David S, Siebert, Reiner, Sun, Xueguang, Tost, Jorg, Walter, Joern, and Zhang, Kun

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Algorithms, DNA, DNA Methylation, DNA Modification Methylases, Genetic Markers, High-Throughput Nucleotide Sequencing, High-Throughput Screening Assays, Promoter Regions, Genetic, Reproducibility of Results, Sensitivity and Specificity, BLUEPRINT consortium
Abstract

DNA methylation patterns are altered in numerous diseases and often correlate with clinically relevant information such as disease subtypes, prognosis and drug response. With suitable assays and after validation in large cohorts, such associations can be exploited for clinical diagnostics and personalized treatment decisions. Here we describe the results of a community-wide benchmarking study comparing the performance of all widely used methods for DNA methylation analysis that are compatible with routine clinical use. We shipped 32 reference samples to 18 laboratories in seven different countries. Researchers in those laboratories collectively contributed 21 locus-specific assays for an average of 27 predefined genomic regions, as well as six global assays. We evaluated assay sensitivity on low-input samples and assessed the assays' ability to discriminate between cell types. Good agreement was observed across all tested methods, with amplicon bisulfite sequencing and bisulfite pyrosequencing showing the best all-round performance. Our technology comparison can inform the selection, optimization and use of DNA methylation assays in large-scale validation studies, biomarker development and clinical diagnostics.

Published
2016

26. Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases

Author

Lynch, Cian J., Bernad, Raquel, Martínez-Val, Ana, Shahbazi, Marta N., Nóbrega-Pereira, Sandrina, Calvo, Isabel, Blanco-Aparicio, Carmen, Tarantino, Carolina, Garreta, Elena, Richart-Ginés, Laia, Alcazar, Noelia, Graña-Castro, Osvaldo, Gómez-Lopez, Gonzalo, Aksoy, Irene, Muñoz-Martín, Maribel, Martinez, Sonia, Ortega, Sagrario, Prieto, Susana, Simboeck, Elisabeth, Camasses, Alain, Stephan-Otto Attolini, Camille, Fernandez, Agustin F., Sierra, Marta I., Fraga, Mario F., Pastor, Joaquin, Fisher, Daniel, Montserrat, Nuria, Savatier, Pierre, Muñoz, Javier, Zernicka-Goetz, Magdalena, and Serrano, Manuel

Published
2020
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27. Genome-wide DNA methylation changes with age in disease-free human skeletal muscle.

Author

Zykovich, Artem, Hubbard, Alan, Flynn, James, Tarnopolsky, Mark, Fraga, Mario, Kerksick, Chad, Ogborn, Dan, MacNeil, Lauren, Mooney, Sean, and Melov, Simon

Subjects
DNA methylation, epigenome, genomics, human aging, postmitotic, skeletal muscle, Adolescent, Adult, Aged, Aging, Base Composition, CpG Islands, DNA Methylation, Gene Expression Regulation, Gene Ontology, Genome, Human, Humans, Male, Muscle, Skeletal, Signal Transduction, Young Adult
Abstract

A decline in skeletal muscle mass and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report for the first time a genome-wide study of DNA methylation dynamics in skeletal muscle of healthy male individuals during normal human aging. We predominantly observed hypermethylation throughout the genome within the aged group as compared to the young subjects. Differentially methylated CpG (dmCpG) nucleotides tend to arise intragenically and are underrepresented in promoters and are overrepresented in the middle and 3 end of genes. The intragenic methylation changes are overrepresented in genes that guide the formation of the junction of the motor neuron and myofibers. We report a low level of correlation of gene expression from previous studies of aged muscle with our current analysis of DNA methylation status. For those genes that had both changes in methylation and gene expression with age, we observed a reverse correlation, with the exception of intragenic hypermethylated genes that were correlated with an increased gene expression. We suggest that a minimal number of dmCpG sites or select sites are required to be altered in order to correlate with gene expression changes. Finally, we identified 500 dmCpG sites that perform well in discriminating young from old samples. Our findings highlight epigenetic links between aging postmitotic skeletal muscle and DNA methylation.

Published
2014

28. A complex interplay between H2A.Z and HP1 isoforms regulates pericentric heterochromatin

Author

González, Jessica, primary, Bosch-Presegué, Laia, additional, Marazuela-Duque, Anna, additional, Guitart-Solanes, Anna, additional, Espinosa-Alcantud, María, additional, Fernandez, Agustín F., additional, Brown, Jeremy P., additional, Ausió, Juan, additional, Vazquez, Berta N., additional, Singh, Prim B., additional, Fraga, Mario F., additional, and Vaquero, Alejandro, additional

Published
2023
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29. Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis

Author

Duruisseaux, Michäel, Martínez-Cardús, Anna, Calleja-Cervantes, Maria E, Moran, Sebastian, Castro de Moura, Manuel, Davalos, Veronica, Piñeyro, David, Sanchez-Cespedes, Montse, Girard, Nicolas, Brevet, Marie, Giroux-Leprieur, Etienne, Dumenil, Coraline, Pradotto, Monica, Bironzo, Paolo, Capelletto, Enrica, Novello, Silvia, Cortot, Alexis, Copin, Marie-Christine, Karachaliou, Niki, Gonzalez-Cao, Maria, Peralta, Sergio, Montuenga, Luis M, Gil-Bazo, Ignacio, Baraibar, Iosune, Lozano, Maria D, Varela, Mar, Ruffinelli, Jose C, Palmero, Ramon, Nadal, Ernest, Moran, Teresa, Perez, Lidia, Ramos, Immaculada, Xiao, Qingyang, Fernandez, Agustin F, Fraga, Mario F, Gut, Marta, Gut, Ivo, Teixidó, Cristina, Vilariño, Noelia, Prat, Aleix, Reguart, Noemi, Benito, Amparo, Garrido, Pilar, Barragan, Isabel, Emile, Jean-François, Rosell, Rafael, Brambilla, Elisabeth, and Esteller, Manel

Published
2018
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30. DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease

Author

Sanchez-Mut, Jose V., Aso, Ester, Panayotis, Nicolas, Lott, Ira, Dierssen, Mara, Rabano, Alberto, Urdinguio, Rocio G., Fernandez, Agustin F., Astudillo, Aurora, Martin-Subero, Jose I., Balint, Balazs, Fraga, Mario F., Gomez, Antonio, Gurnot, Cecile, Roux, Jean-Christophe, Avila, Jesus, Hensch, Takao K., Ferrer, Isidre, and Esteller, Manel

Abstract

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

Published
2013

31. Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Author

Janin, Maxime, Ortiz-Barahona, Vanessa, de Moura, Manuel Castro, Martínez-Cardús, Anna, Llinàs-Arias, Pere, Soler, Marta, Nachmani, Daphna, Pelletier, Joffrey, Schumann, Ulrike, Calleja-Cervantes, Maria E., Moran, Sebastian, Guil, Sonia, Bueno-Costa, Alberto, Piñeyro, David, Perez-Salvia, Montserrat, Rosselló-Tortella, Margalida, Piqué, Laia, Bech-Serra, Joan J., De La Torre, Carolina, Vidal, August, Martínez-Iniesta, María, Martín-Tejera, Juan F., Villanueva, Alberto, Arias, Alexandra, Cuartas, Isabel, Aransay, Ana M., La Madrid, Andres Morales, Carcaboso, Angel M., Santa-Maria, Vicente, Mora, Jaume, Fernandez, Agustin F., Fraga, Mario F., Aldecoa, Iban, Pedrosa, Leire, Graus, Francesc, Vidal, Noemi, Martínez-Soler, Fina, Tortosa, Avelina, Carrato, Cristina, Balañá, Carme, Boudreau, Matthew W., Hergenrother, Paul J., Kötter, Peter, Entian, Karl-Dieter, Hench, Jürgen, Frank, Stephan, Mansouri, Sheila, Zadeh, Gelareh, Dans, Pablo D., Orozco, Modesto, Thomas, George, Blanco, Sandra, Seoane, Joan, Preiss, Thomas, Pandolfi, Pier Paolo, and Esteller, Manel

Published
2019
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32. Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma

Author

Vázquez-Domínguez, Irene, González-Sánchez, Laura, López-Nieva, Pilar, Fernández-Navarro, Pablo, Villa-Morales, María, Cobos-Fernández, María Á., Sastre, Isabel, F. Fraga, Mario, F. Fernández, Agustín, Malumbres, Marcos, Salazar-Roa, María, Graña-Castro, Osvaldo, Santos, Javier, Llamas, Pilar, López-Lorenzo, José L., and Fernández-Piqueras, José

Published
2019
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33. Epigenetic Differences Arise during the Lifetime of Monozygotic Twins

Author

Fraga, Mario F., Ballestar, Esteban, Paz, Maria F., Ropero, Santiago, Setien, Fernando, Ballestar, Maria L., Heine-Suñer, Damia, Cigudosa, Juan C., Urioste, Miguel, Benitez, Javier, Boix-Chornet, Manuel, Sanchez-Aguilera, Abel, Ling, Charlotte, Carlsson, Emma, Poulsen, Pernille, Vaag, Allan, Stephan, Zarko, Spector, Tim D., Wu, Yue-Zhong, Plass, Christoph, Esteller, Manel, and Gartler, Stanley M.

Published
2005

34. A human genome editing-based MLL::AF4 B-cell ALL model recapitulates key cellular and molecular leukemogenic features

Author

Bueno, Clara, primary, Torres-Ruíz, Raul, additional, Velasco-Hernandez, Talia, additional, Molina, Oscar, additional, Petazzi, Paolo, additional, Martinez-Moreno, Alba, additional, Rodríguez-Cortez, Virginia Carolina, additional, Vinyoles, Meritxell, additional, Cantilena, Sandra, additional, Williams, Owen, additional, Vega-García, Nerea, additional, Rodriguez-Perales, Sandra, additional, Segovia, José Carlos, additional, Quintana-Bustamante, Oscar, additional, Roy, Anindita, additional, Meyer, Claus, additional, Marschalek, Rolf, additional, Smith, Alastair, additional, Milne, Thomas A., additional, Fraga, Mario F., additional, Tejedor, Juan Ramón Ramón, additional, and Menendez, Pablo, additional

Published
2023
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35. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma

Author

Rey, Verónica, primary, Tornín, Juan, additional, Alba-Linares, Juan Jose, additional, Robledo, Cristina, additional, Murillo, Dzohara, additional, Rodríguez, Aida, additional, Gallego, Borja, additional, Huergo, Carmen, additional, Braña, Alejandro, additional, Astudillo, Aurora, additional, Heymann, Dominique, additional, Fernández, Agustín F., additional, Fraga, Mario F., additional, Alonso, Javier, additional, and Rodríguez, René, additional

Published
2023
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37. Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation.

Author

Villa-Fernández, Elsa, García, Ana Victoria, Fernández-Fernández, Alejandra, García-Villarino, Miguel, Ares-Blanco, Jessica, Pujante, Pedro, González-Vidal, Tomás, Fraga, Mario F., Torre, Edelmiro Menéndez, Delgado, Elias, and Lambert, Carmen

Subjects
METFORMIN, RHODOPSIN, CHROMATOPHORES, CELL proliferation, CELL survival, EPITHELIAL cells, CELL culture
Abstract

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin's are being analysed. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Contributors

Author

Ait-Si-Ali, Slimane, primary, Albini, Sonia, additional, Atzmon, Gil, additional, Badylak, Stephen F., additional, Barnstable, C.J., additional, Biferali, Beatrice, additional, Caporale, Nicolò, additional, Chen, Zhaoyi, additional, Chiacchiera, Fulvio, additional, Coffman, James A., additional, D’Angelo, William, additional, Dean, Wendy, additional, Eriksson, Jonas, additional, Fernández, Agustín F., additional, Fraga, Mario F., additional, Guil, Sònia, additional, Gutman, Danielle, additional, Hadi, Nur Annies Abd, additional, Hanna, Courtney W., additional, Josipović, Nataša, additional, Julian, Lisa M., additional, Mai, Antonello, additional, Marelli, Luca, additional, McCarthy, Ryan L., additional, McLaughlin, Katy A., additional, Meehan, Richard R., additional, Mozzetta, Chiara, additional, Nicetto, Dario, additional, Oliveira-Mateos, Cristina, additional, Ottaviano, Raffaele, additional, Pagiatakis, Christina, additional, Palacios, Daniela, additional, Papait, Roberto, additional, Papantonis, Argyris, additional, Pennings, Sari, additional, Pérez, Raúl F., additional, Petchreing, Petchroi, additional, Pietrobon, Adam, additional, Popova, E.Y., additional, Revuelta, Ailsa, additional, Sánchez-Castillo, Anaís, additional, Santamarina, Pablo, additional, Serio, Simone, additional, Stanford, William L., additional, Stazi, Giulia, additional, Testa, Giuseppe, additional, Valente, Sergio, additional, Viscomi, Maria Teresa, additional, Zakharova, Vlada, additional, Zaret, Kenneth S., additional, and Zwergel, Clemens, additional

Published
2019
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41. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Author

Mueller, Sebastian, Engleitner, Thomas, Maresch, Roman, Zukowska, Magdalena, Lange, Sebastian, Kaltenbacher, Thorsten, Konukiewitz, Bjrn, llinger, Rupert, Zwiebel, Maximilian, Strong, Alex, Yen, Hsi-Yu, Banerjee, Ruby, Louzada, Sandra, Fu, Beiyuan, Seidler, Barbara, Gtzfried, Juliana, Schuck, Kathleen, Hassan, Zonera, Arbeiter, Andreas, Schnhuber, Nina, Klein, Sabine, Veltkamp, Christian, Friedrich, Mathias, Rad, Lena, Barenboim, Maxim, Ziegenhain, Christoph, Hess, Julia, Dovey, Oliver M., Eser, Stefan, Parekh, Swati, Constantino-Casas, Fernando, de la Rosa, Jorge, Sierra, Marta I., Fraga, Mario, Mayerle, Julia, Klppel, Gnter, Cadianos, Juan, Liu, Pentao, Vassiliou, George, Weichert, Wilko, Steiger, Katja, Enard, Wolfgang, Schmid, Roland M., Yang, Fengtang, Unger, Kristian, Schneider, Gnter, Varela, Ignacio, Bradley, Allan, Saur, Dieter, and Rad, Roland

Subjects
Phenotypes -- Research, Cell culture -- Research, Pancreatic cancer -- Genetic aspects -- Physiological aspects, Biological research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras[sup.MUT] levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous Kras[sup.MUT] in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgf-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer., Author(s): Sebastian Mueller [1, 2]; Thomas Engleitner [1, 2, 3]; Roman Maresch [1, 2, 3]; Magdalena Zukowska [1, 2]; Sebastian Lange [1, 2]; Thorsten Kaltenbacher [1, 2, 3]; Bjrn Konukiewitz [...]

Published
2018
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42. Enhanced detection of viral RNA species using fokI-assisted digestion of DNA duplexes and DNA/RNA hybrids

Author

Instituto de Salud Carlos III, European Commission, Consejo Superior de Investigaciones Científicas (España), Principado de Asturias, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Instituto Universitario de Oncología del Principado de Asturias, Tejedor, Juan Ramón [0000-0002-4061-9698], Fraga, Mario F. [0000-0001-8450-2603], Tejedor, Juan Ramón, Martín, Gabriel, Roberti, Annalisa, Mangas, Cristina, Santamarina-Ojeda, Pablo, Pérez, Raúl F., López, Virginia, Urdinguio, Rocío G., Alba-Linares, Juan J., Peñarroya, Alfonso, Álvarez-Argüelles, Marta E., Boga, José A., Fernández, Agustín F., Rojo-Alba, Susana, Fraga, Mario F., Instituto de Salud Carlos III, European Commission, Consejo Superior de Investigaciones Científicas (España), Principado de Asturias, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Instituto Universitario de Oncología del Principado de Asturias, Tejedor, Juan Ramón [0000-0002-4061-9698], Fraga, Mario F. [0000-0001-8450-2603], Tejedor, Juan Ramón, Martín, Gabriel, Roberti, Annalisa, Mangas, Cristina, Santamarina-Ojeda, Pablo, Pérez, Raúl F., López, Virginia, Urdinguio, Rocío G., Alba-Linares, Juan J., Peñarroya, Alfonso, Álvarez-Argüelles, Marta E., Boga, José A., Fernández, Agustín F., Rojo-Alba, Susana, and Fraga, Mario F.

Abstract

The accurate detection of nucleic acids from certain biological pathogens is critical for the diagnosis of human diseases. However, amplified detection of RNA molecules from a complex sample by direct detection of RNA/DNA hybrids remains a challenge. Here, we show that type IIS endonuclease FokI is able to digest DNA duplexes and DNA/RNA hybrids when assisted by a dumbbell-like fluorescent sensing oligonucleotide. As proof of concept, we designed a battery of sensing oligonucleotides against specific regions of the SARS-CoV-2 genome and interrogated the role of FokI relaxation as a potential nicking enzyme for fluorescence signal amplification. FokI-assisted digestion of SARS-CoV-2 probes increases the detection signal of ssDNA and RNA molecules and decreases the limit of detection more than 3.5-fold as compared to conventional molecular beacon approaches. This cleavage reaction is highly specific to its target molecules, and no detection of other highly related B-coronaviruses was observed in the presence of complex RNA mixtures. In addition, the FokI-assisted reaction has a high multiplexing potential, as the combined detection of different viral RNAs, including different SARS-CoV-2 variants, was achieved in the presence of multiple combinations of fluorophores and sensing oligonucleotides. When combined with isothermal rolling circle amplification technologies, FokI-assisted digestion reduced the detection time of SARS-CoV-2 in COVID-19-positive human samples with adequate sensitivity and specificity compared to conventional reverse transcription polymerase chain reaction approaches, highlighting the potential of FokI-assisted signal amplification as a valuable sensing mechanism for the detection of human pathogens.

Published
2022

43. Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia

Author

Tejedor, Juan Ramon, Bueno, Clara, Vinyoles, Meritxell, Petazzi, Paolo, Agraz- Doblas, Antonio, Cobo, Isabel, Torres-Ruiz, Raul, Bayon, Gustavo F., Perez, Raul F., Lopez-Tamargo, Sara, Gutierrez-Aguera, Francisco, Santamarina-Ojeda, Pablo, Ramirez-Orellana, Manuel, Bardini, Michela, Cazzaniga, Giovanni, Ballerini, Paola, Schneider, Pauline, Stam, Ronald W., Varela, Ignacio, Fraga, Mario F., Fernandez, Agustin F., and Menendez, Pablo

Subjects
Gene mutations -- Research, B cells -- Genetic aspects -- Health aspects, Acute lymphocytic leukemia -- Genetic aspects -- Development and progression, Epigenetic inheritance -- Research, Pediatric research, Leukemia in children -- Genetic aspects -- Development and progression, Health care industry
Abstract

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB- ALL patient-derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL., Introduction B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer (1). Current long-term survival rates for pediatric B-ALL approach approximately 85%. However, infant B-ALL (iB-ALL) ( In [...]

Published
2021
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44. Data from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Author

Carmona, F. Javier, primary, Azuara, Daniel, primary, Berenguer-Llergo, Antonio, primary, Fernández, Agustin F., primary, Biondo, Sebastiano, primary, de Oca, Javier, primary, Rodriguez-Moranta, Francisco, primary, Salazar, Ramón, primary, Villanueva, Alberto, primary, Fraga, Mario F., primary, Guardiola, Jordi, primary, Capellá, Gabriel, primary, Esteller, Manel, primary, and Moreno, Victor, primary

Published
2023
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45. Supplementary Methods from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Author

Carmona, F. Javier, primary, Azuara, Daniel, primary, Berenguer-Llergo, Antonio, primary, Fernández, Agustin F., primary, Biondo, Sebastiano, primary, de Oca, Javier, primary, Rodriguez-Moranta, Francisco, primary, Salazar, Ramón, primary, Villanueva, Alberto, primary, Fraga, Mario F., primary, Guardiola, Jordi, primary, Capellá, Gabriel, primary, Esteller, Manel, primary, and Moreno, Victor, primary

Published
2023
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46. Supplementary Tables 1-4 from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Author

Carmona, F. Javier, primary, Azuara, Daniel, primary, Berenguer-Llergo, Antonio, primary, Fernández, Agustin F., primary, Biondo, Sebastiano, primary, de Oca, Javier, primary, Rodriguez-Moranta, Francisco, primary, Salazar, Ramón, primary, Villanueva, Alberto, primary, Fraga, Mario F., primary, Guardiola, Jordi, primary, Capellá, Gabriel, primary, Esteller, Manel, primary, and Moreno, Victor, primary

Published
2023
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47. Supplementary Figures 1-6 from DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Author

Carmona, F. Javier, primary, Azuara, Daniel, primary, Berenguer-Llergo, Antonio, primary, Fernández, Agustin F., primary, Biondo, Sebastiano, primary, de Oca, Javier, primary, Rodriguez-Moranta, Francisco, primary, Salazar, Ramón, primary, Villanueva, Alberto, primary, Fraga, Mario F., primary, Guardiola, Jordi, primary, Capellá, Gabriel, primary, Esteller, Manel, primary, and Moreno, Victor, primary

Published
2023
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48. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Principado de Asturias, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (CSIC), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Fundación la Caixa, Gobierno Vasco, Roberti, Annalisa, Tejedor, Juan Ramón, Díaz Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández Morera, Juan Luis, Díaz Quintana, Antonio Jesús, Amo, Vicente del, Fernández, Agustín F., Fraga, Mario F., Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Principado de Asturias, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (CSIC), Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Fundación la Caixa, Gobierno Vasco, Roberti, Annalisa, Tejedor, Juan Ramón, Díaz Moreno, Irene, López, Virginia, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Urdinguio, Rocío G., Concellón, Carmen, Martínez-Chantar, María Luz, Fernández Morera, Juan Luis, Díaz Quintana, Antonio Jesús, Amo, Vicente del, Fernández, Agustín F., and Fraga, Mario F.

Abstract

Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.

Published
2023

49. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, Martínez-Chantar, María Luz, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, and Martínez-Chantar, María Luz

Abstract

Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Published
2023

50. Biomarcadores de metilación del ADN para el diagnóstico precoz del cáncer de tiroides

Author

Delgado-Álvarez, Elías, Fraga, Mario F., Asociación Española Contra el Cáncer, Principado de Asturias, Instituto de Salud Carlos III, Fundación General CSIC, Liberbank, Obra Social Cajastur, European Commission, Morales, Paula, Delgado-Álvarez, Elías, Fraga, Mario F., Asociación Española Contra el Cáncer, Principado de Asturias, Instituto de Salud Carlos III, Fundación General CSIC, Liberbank, Obra Social Cajastur, European Commission, and Morales, Paula

Abstract

[ES] Los nódulos tiroideos son la patología endocrina más frecuente, diagnosticándose malignidad en una pequeña proporción (∼15 %). La incidencia del cáncer de tiroides se ha triplicado en España en los últimos 25 años. Así mismo, afecta tres veces más a mujeres que a hombres y se incrementa su frecuencia con la edad, sobre todo a partir de los 40 años. En general, son tumores de gran pronóstico, con tasas de supervivencia cercanas al 100 %. Sin embargo, debido a la alta prevalencia de los nódulos en la población es necesario un triaje exhaustivo. La punción por aspiración con aguja fina es la prueba no quirúrgica de referencia para el diagnóstico inicial de los nódulos tiroideos. Sin embargo, el 25-30 % de todas las punciones son designadas como indeterminadas y dada que la posibilidad de malignidad, muchos pacientes suelen ser derivados a cirugía. Tras la operación, solo el 25 % de las lesiones resultan malignas, por lo que el riesgo de cáncer no es lo suficientemente alto como para respaldar definitivamente la cirugía. En retrospectiva, estas tiroidectomías son innecesarias y generan complicaciones que los pacientes padecerán durante toda su vida. Por lo tanto, existe una necesidad urgente de desarrollar métodos efectivos para discernir benignidad de malignidad en las lesiones foliculares de tiroides. El desarrollo de biomarcadores seguros y rentables podría ayudar en la toma de decisiones del médico tratante para manejar con mayor certeza los nódulos tiroideos. Si bien durante mucho tiempo se ha tratado de establecer el valor diagnóstico de las diferentes alteraciones genéticas ninguna parece ser totalmente resolutiva. La metilación del ADN es una de las principales modificaciones epigenéticas y su papel en el inicio, desarrollo y metástasis de cánceres humanos ha sido ampliamente descrito, incluido en cáncer de tiroides. Dado que las firmas de metilación del ADN pueden ser indicativas de la plasticidad molecular que surge en la tumorigénesis temprana, en este e, [EN] Thyroid nodules are the most common encountered thyroid endocrine pathology, being unfrequently diagnosed as malignant (∼15%). The incidence of thyroid cancer has tripled in Spain in the last 25 years. Likewise, it affects three times more women than men and its frequency increases with age, especially after the age of 40. In general, they are tumors with a great prognosis, with survival rates close to 100%. However, due to the high prevalence of nodules in the population, an exhaustive triage is necessary. Fine needle aspiration puncture is the gold standard non-surgical test for the initial diagnosis of thyroid nodules. However, 25-30% of all cytologies are designated as indeterminate and given the possibility of malignancy, many patients are often referred for surgery. After the operation, only 25% of lesions result as cancer, so the risk of malignancy is not high enough to definitively support thyroidectomy. In hindsight, these thyroidectomies are necessary and lead to complications that patients will endure for their entire lives. Therefore, there is an urgent need to develop effective methods to discern benign from malignant follicular-patterned thyroid lesions. Safe and cost-effective biomarkers could help in the decision-making of the treating physician to manage thyroid nodules with greater certainty. Although many attempts have been made to establish the diagnostic value of the different genetic alterations, none of them seems to be fully resolvable. DNA methylation is one of the main epigenetic modifications and its role in the initiation, development and metastasis of human cancers has been widely described, including thyroid cancer. Since DNA methylation signatures may be indicative of molecular plasticity that arises in early tumorigenesis, this study postulated that this epigenetic mark could be used as a marker for discrimination in difficult-to-diagnose cases. Initially, mutation analysis was performed by whole-exome sequencing in a retrospecti

Published
2023

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