Author: "Urdinguio, Rocío G." - Searchworks@Jio Institute Digital Library Search Results

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111 results on '"Urdinguio, Rocío G."'

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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2. 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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3. Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis

Author: Roberti, Annalisa, Tejedor, Juan Ramon, 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, del Amo, Vicente, Fernández, Agustín F., and Fraga, Mario F.
Published: 2023
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4. 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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5. Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes

Author: Pérez, Raúl F., Santamarina, Pablo, Tejedor, Juan Ramón, Urdinguio, Rocío G., Álvarez-Pitti, Julio, Redon, Pau, Fernández, Agustín F., Fraga, Mario F., and Lurbe, Empar
Published: 2019
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6. 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

7. 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

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

Author: Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Fundación General CSIC, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Ramón Areces, Junta de Andalucía, Fundación la Caixa, Consejo Superior de Investigaciones Científicas (España), Instituto Universitario de Oncología del Principado de Asturias, Eusko Jaurlaritza, Liberbank, Obra Social Cajastur, Ministerio de Economía y Competitividad (España), 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 L., Díaz-Quintana, Antonio, Amo, Vicente del, Fernández, Agustín F., Fraga, Mario F., Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Fundación General CSIC, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Ramón Areces, Junta de Andalucía, Fundación la Caixa, Consejo Superior de Investigaciones Científicas (España), Instituto Universitario de Oncología del Principado de Asturias, Eusko Jaurlaritza, Liberbank, Obra Social Cajastur, Ministerio de Economía y Competitividad (España), 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 L., Díaz-Quintana, Antonio, 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

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

Author: Instituto de Salud Carlos III, European Commission, Asociación Española Contra el Cáncer, Principado de Asturias, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Ministerio de Universidades (España), 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., Fraga, Mario F., Instituto de Salud Carlos III, European Commission, Asociación Española Contra el Cáncer, Principado de Asturias, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Ministerio de Universidades (España), 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.
Abstract: [Background]: Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated., [Results]: In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence., [Conclusions]: These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.
Published: 2023

10. CRISPR/dCas9-mediated DNA demethylation screen identifies driver epigenetic determinants of colorectal cancer (Processed data)

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., Fraga, Mario F., 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.
Abstract: [Background]: Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is an actual driver of cancer or is a mere consequence of the carcinogenic process remains to be elucidated., [Results]: In this work we performed an integrative multi -omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a custom arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of such DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact in the reactivation of gene expression and in the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence., [Conclusions]: These results highlight the potential role of DNA methylation as a driver mechanism of CRC and open up the venue for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.
Published: 2023

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

Author: Goikoetxea-Usandizaga, Naroa, primary, Bravo, Miren, additional, Egia-Mendikute, Leire, additional, Abecia, Leticia, additional, Serrano-Maciá, Marina, additional, Urdinguio, Rocío G., additional, Clos-García, Marc, additional, Rodríguez-Agudo, Rubén, additional, Araujo-Legido, Raquel, additional, López-Bermudo, Lucía, additional, Delgado, Teresa C., additional, Lachiondo-Ortega, Sofía, additional, González-Recio, Irene, additional, Gil-Pitarch, Clàudia, additional, Peña-Cearra, Ainize, additional, Simón, Jorge, additional, Benedé-Ubieto, Raquel, additional, Ariño, Silvia, additional, Herranz, Jose M., additional, Azkargorta, Mikel, additional, Salazar-Bermeo, Julio, additional, Martí, Nuria, additional, Varela-Rey, Marta, additional, Falcón-Pérez, Juan M., additional, Lorenzo, Óscar, additional, Nogueiras, Rubén, additional, Elortza, Félix, additional, Nevzorova, Yulia A., additional, Cubero, Francisco J., additional, Saura, Domingo, additional, Martínez-Cruz, Luis Alfonso, additional, Sabio, Guadalupe, additional, Palazón, Asís, additional, Sancho-Bru, Pau, additional, Elguezabal, Natalia, additional, Fraga, Mario F., additional, Ávila, Matías A., additional, Bataller, Ramón, additional, Marín, José J.G., additional, Martín, Franz, additional, and Martínez-Chantar, María Luz, additional
Published: 2023
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12. Role of Epigenetics in Neural Differentiation: Implications for Health and Disease

Author: Toraño, Estela G., Fernandez, Agustin F., Urdinguio, Rocio G., Fraga, Mario F., Maulik, Nilanjana, editor, and Karagiannis, Tom, editor
Published: 2014
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13. A DNA methylation signature associated with aberrant promoter DNA hypermethylation of DNMT3B in human colorectal cancer

Author: Huidobro, Covadonga, Urdinguio, Rocío G., Rodríguez, Ramón María, Mangas, Cristina, Calvanese, Vincenzo, Martínez-Camblor, Pablo, Ferrero, Cecilia, Parra-Blanco, Adolfo, Rodrigo, Luis, Obaya, Álvaro J., Suárez-Fernández, Laura, Astudillo, Aurora, Hernando, Henar, Ballestar, Esteban, Fernández, Agustín F., and Fraga, Mario F.
Published: 2012
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14. Supporting Information - Enhanced detection of viral RNA species using fokI-assisted digestion of DNA duplexes and DNA/RNA hybrids

Author: 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., 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: List of sequences used in this work, FokI-assisted digestion of DNA duplexes and DNA/RNA hybrids, digestion of DNA duplexes and DNA/RNA hybrids mediated by BanI and FokI, working principle of the FokI-assisted digestion method, design of target DNA/RNA sequences and reporter oligonucleotides, LOD of the proposed reactions, enhanced detection of individual SARS-CoV-2 sequences, FokI-assisted signal amplification allows the simultaneous detection of multiple targets, FokI-assisted signal amplification discriminates between known SARS-CoV-2 variants, and specificity and LOD of the RCA-enhanced reaction.
Published: 2022

15. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Author: Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Association de la Recherche Contre le Cancer (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, Institut National du Cancer (France), Fondation Leducq, Université de Paris, Biotechnology and Biological Sciences Research Council (UK), European Research Council, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Chondronasiou, Dafni, Gill, Diljeet, Mosteiro, Lluc, Urdinguio, Rocío G., Berenguer-Llergo, Antonio, Aguilera,Mònica, Durand, Sylvère, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Abad, Maria, Martin-Herranz, Daniel E., Stephan-Otto Attolini, Camille, Prats, Neus, Kroemer, Guido, Fraga, Mario F., Reik, Wolf, Serrano, Manuel, Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Association de la Recherche Contre le Cancer (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, Institut National du Cancer (France), Fondation Leducq, Université de Paris, Biotechnology and Biological Sciences Research Council (UK), European Research Council, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Chondronasiou, Dafni, Gill, Diljeet, Mosteiro, Lluc, Urdinguio, Rocío G., Berenguer-Llergo, Antonio, Aguilera,Mònica, Durand, Sylvère, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Abad, Maria, Martin-Herranz, Daniel E., Stephan-Otto Attolini, Camille, Prats, Neus, Kroemer, Guido, Fraga, Mario F., Reik, Wolf, and Serrano, Manuel
Abstract: The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
Published: 2022

16. Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

Author: Generalitat de Catalunya, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundació Privada Cellex, Fundación la Caixa, García-Prieto, Carlos A., Villanueva, Lorea, Bueno-Costa, Alberto, Davalos, Veronica, González-Navarro, Europa Azucena, Juan, Manel, Urbano-Ispizua, Álvaro, Delgado, Julio, Ortiz-Maldonado, Valentín, Bufalo, Francesca del, Locatelli, Franco, Quintarelli, Concetta, Sinibaldi, Matilde, Soler, Marta, Castro de Moura, Manuel, Ferrer, Gerardo, Urdinguio, Rocío G., Fernández, Agustín F., Fraga, Mario F., Bar, Diana, Meir, Amilia, Itzhaki, Orit, Besser, Michal, J., Avigdor, Abraham, Jacoby, Elad, Esteller, Manel, Generalitat de Catalunya, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundació Privada Cellex, Fundación la Caixa, García-Prieto, Carlos A., Villanueva, Lorea, Bueno-Costa, Alberto, Davalos, Veronica, González-Navarro, Europa Azucena, Juan, Manel, Urbano-Ispizua, Álvaro, Delgado, Julio, Ortiz-Maldonado, Valentín, Bufalo, Francesca del, Locatelli, Franco, Quintarelli, Concetta, Sinibaldi, Matilde, Soler, Marta, Castro de Moura, Manuel, Ferrer, Gerardo, Urdinguio, Rocío G., Fernández, Agustín F., Fraga, Mario F., Bar, Diana, Meir, Amilia, Itzhaki, Orit, Besser, Michal, J., Avigdor, Abraham, Jacoby, Elad, and Esteller, Manel
Abstract: Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02
Published: 2022

17. 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

18. Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility

Author: Urdinguio, Rocío G., Bayón, Gustavo F., Dmitrijeva, Marija, Toraño, Estela G., Bravo, Cristina, Fraga, Mario F., Bassas, Lluís, Larriba, Sara, and Fernández, Agustín F.
Published: 2015
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19. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies

Author: Urdinguio, Rocio G, Sanchez-Mut, Jose V, and Esteller, Manel
Published: 2009
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20. A DNA methylation signature associated with the epigenetic repression of glycine N-methyltransferase in human hepatocellular carcinoma

Author: Huidobro, Covadonga, Toraño, Estela G., Fernández, Agustín F., Urdinguio, Rocío G., Rodríguez, Ramón M., Ferrero, Cecilia, Martínez-Camblor, Pablo, Boix, Loreto, Bruix, Jordi, García-Rodríguez, Juan Luís, Varela-Rey, Marta, Mato, José María, Martínez-Chantar, María Luz, and Fraga, Mario F.
Published: 2013
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21. Epigenetic Deregulation of the Histone Methyltransferase KMT5B Contributes to Malignant Transformation in Glioblastoma

Author: López, Virginia, primary, Tejedor, Juan Ramón, additional, Carella, Antonella, additional, García, María G., additional, Santamarina-Ojeda, Pablo, additional, Pérez, Raúl F., additional, Mangas, Cristina, additional, Urdinguio, Rocío G., additional, Aranburu, Aitziber, additional, de la Nava, Daniel, additional, Corte-Torres, María D., additional, Astudillo, Aurora, additional, Mollejo, Manuela, additional, Meléndez, Bárbara, additional, Fernández, Agustín F., additional, and Fraga, Mario F., additional
Published: 2021
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22. Frequent aberrant expression of the human ether à go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications

Author: Menéndez, Sofía Tirados, Villaronga, María Ángeles, Rodrigo, Juan P., Álvarez-Teijeiro, Saúl, García-Carracedo, Darío, Urdinguio, Rocío G., Fraga, Mario F., Pardo, Luis A., Viloria, Cristina Gutiérrez, Suárez, Carlos, and García-Pedrero, Juana María
Published: 2012
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23. Epigenomics and life style

Author: Fraga, Mario F., Ramos, Sonia, Bravo, Laura, Collado, María Carmen, Fernández Pérez, Raúl, Gómara, B., Urdinguio, Rocío G., Martín, M. Ángeles, Herrero, Antonia, and Ramos, Lourdes
Abstract: CSIC Scientific Challenges: Towards 2030, That epigenetic changes during lifetime (i.e. those with a biological purpose, epigenetic drift and epigenetic clocks) depend on a complex mixture of factors is well-known, as is the fact that, depending on the loci, they can be modulated by genetic and/or external factors, lifestyle being one of the most important. However, the underlying molecular mechanism remains largely unknown and addressing this will be an important challenge for CSIC in this field.
Published: 2021

24. Physical exercise shapes the mouse brain epigenome

Author: Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Fundación General CSIC, Instituto de Salud Carlos III, Fundación Tatiana Pérez de Guzmán el Bueno, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Universidad de Oviedo, Liberbank, Obra Social Cajastur, Urdinguio, Rocío G., Tejedor, Juan Ramón, 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, Fernández, Agustín F., Fraga, Mario F., Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Fundación General CSIC, Instituto de Salud Carlos III, Fundación Tatiana Pérez de Guzmán el Bueno, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Universidad de Oviedo, Liberbank, Obra Social Cajastur, Urdinguio, Rocío G., Tejedor, Juan Ramón, 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, Fernández, Agustín F., and Fraga, Mario F.
Abstract: [Objective]: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice., [Methods]: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function., [Results]: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions., [Conclusions]: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research.
Published: 2021

25. Conservation of aging and cancer epigenetic signatures across human and mouse

Author: Pérez, Raúl F. [0000-0003-4336-9898], Tejedor, Juan Ramón [0000-0002-4061-9698], Santamarina-Ojeda, Pablo [0000-0002-7439-8467], Fernández, Agustín F. [0000-0002-3792-4085], Fraga, Mario F. [0000-0001-8450-2603], Pérez, Raúl F., Tejedor, Juan Ramón, Santamarina-Ojeda, Pablo, López, Virginia, Urdinguio, Rocío G., Villamañán, Lucía, Candiota, Ana Paula, Vidal Sarró, Noemí, Barradas, Marta, Fernández-Marcos, Pablo José, Serrano, Manuel, Fernández, Agustín F., Fraga, Mario F., Pérez, Raúl F. [0000-0003-4336-9898], Tejedor, Juan Ramón [0000-0002-4061-9698], Santamarina-Ojeda, Pablo [0000-0002-7439-8467], Fernández, Agustín F. [0000-0002-3792-4085], Fraga, Mario F. [0000-0001-8450-2603], Pérez, Raúl F., Tejedor, Juan Ramón, Santamarina-Ojeda, Pablo, López, Virginia, Urdinguio, Rocío G., Villamañán, Lucía, Candiota, Ana Paula, Vidal Sarró, Noemí, Barradas, Marta, Fernández-Marcos, Pablo José, Serrano, Manuel, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Aging and cancer are two interrelated biological processes, with aging being one of the most important risk factors for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been identified in recent literature. While many of these observations arise from the use of mouse models, there is a lack of systematic and single-base resolution comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are especially significant with respect to the DNA methylation alterations found independently in the two species as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and non-tumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally we integrated our data in order to study interspecies DNA methylation levels at specific CpG sites. Globally, we found robust evidence for the conservation of cancer and aging-associated epigenomic patterns in both species, and our observations point towards the preservation of the functional consequences of these alterations at multiple levels of genomic regulation.
Published: 2021

26. Stability of imprinting and differentiation capacity in naïve human cells induced by chemical inhibition of CDK8 and CDK19

Author: Asociación Española Contra el Cáncer, Principado de Asturias, Instituto de Salud Carlos III, European Commission, Obra Social Cajastur, Fundación General CSIC, Liberbank, European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Fundación la Caixa, Bernad, Raquel, Lynch, Cian J., Urdinguio, Rocío G., Stephan-Otto Attolini, Camille, Fraga, Mario F., Serrano, Manuel, Asociación Española Contra el Cáncer, Principado de Asturias, Instituto de Salud Carlos III, European Commission, Obra Social Cajastur, Fundación General CSIC, Liberbank, European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Fundación la Caixa, Bernad, Raquel, Lynch, Cian J., Urdinguio, Rocío G., Stephan-Otto Attolini, Camille, Fraga, Mario F., and Serrano, Manuel
Abstract: Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human naïve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize naïve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8/19i). Long-term cultured CDK8/19i-naïve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8/19i-naïve human PSCs. We report that long-term cultured CDK8/19i-naïve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8/19i-naïve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the naïve state. Interestingly, long-term cultured CDK8/19i-naïve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8/19i-naïve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8/19 stabilizes human PSCs in a functional naïve state that preserves imprinting and
Published: 2021

27. Epigenetic deregulation of the histone methyltransferase KMT5B contributes to malignant transformation in glioblastoma

Author: Instituto de Salud Carlos III, Principado de Asturias, European Commission, Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Liberbank, Fundación para la Investigación y la Innovación Biosanitaria del Principado de Asturias, López, Virginia, Tejedor, Juan Ramón, Carella, Antonella, García, María G., Santamarina-Ojeda, Pablo, Pérez, Raúl F., Mangas, Cristina, Urdinguio, Rocío G., Aranburu, Aitziber, Nava Martín, Daniel de la, Corte-Torres, M. Daniela, Astudillo, Aurora, Mollejo, Manuela, Meléndez, Bárbara, Fernández, Agustín F., Fraga, Mario F., Instituto de Salud Carlos III, Principado de Asturias, European Commission, Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Liberbank, Fundación para la Investigación y la Innovación Biosanitaria del Principado de Asturias, López, Virginia, Tejedor, Juan Ramón, Carella, Antonella, García, María G., Santamarina-Ojeda, Pablo, Pérez, Raúl F., Mangas, Cristina, Urdinguio, Rocío G., Aranburu, Aitziber, Nava Martín, Daniel de la, Corte-Torres, M. Daniela, Astudillo, Aurora, Mollejo, Manuela, Meléndez, Bárbara, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adulthood. Epigenetic mechanisms are known to play a key role in GBM although the involvement of histone methyltransferase KMT5B and its mark H4K20me2 has remained largely unexplored. The present study shows that DNA hypermethylation and loss of DNA hydroxymethylation is associated with KMT5B downregulation and genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Ectopic overexpression of KMT5B induced tumor suppressor-like features in vitro and in a mouse tumor xenograft model, as well as changes in the expression of several glioblastoma-related genes. H4K20me2 enrichment was found immediately upstream of the promoter regions of a subset of deregulated genes, thus suggesting a possible role for KMT5B in GBM through the epigenetic modulation of key target cancer genes.
Published: 2021

28. Conservation of aging and cancer epigenetic signatures across human and mouse

Author: Asociación Española Contra el Cáncer, Fundación General CSIC, European Commission, Instituto de Salud Carlos III, Principado de Asturias, Fundación Ramón Areces, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Universidad Autónoma de Barcelona, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Liberbank, Instituto Madrileño de Investigación y Desarrollo Rural, Agrario y Alimentario, Pérez, Raúl F., Tejedor, Juan Ramón, Santamarina-Ojeda, Pablo, López, Virginia, Urdinguio, Rocío G., Villamañán, Lucía, Candiota, Ana Paula, Vidal Sarró, Noemí, Barradas, Marta, Fernández-Marcos, Pablo José, Serrano, Manuel, Fernández, Agustín F., Fraga, Mario F., Asociación Española Contra el Cáncer, Fundación General CSIC, European Commission, Instituto de Salud Carlos III, Principado de Asturias, Fundación Ramón Areces, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Universidad Autónoma de Barcelona, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Liberbank, Instituto Madrileño de Investigación y Desarrollo Rural, Agrario y Alimentario, Pérez, Raúl F., Tejedor, Juan Ramón, Santamarina-Ojeda, Pablo, López, Virginia, Urdinguio, Rocío G., Villamañán, Lucía, Candiota, Ana Paula, Vidal Sarró, Noemí, Barradas, Marta, Fernández-Marcos, Pablo José, Serrano, Manuel, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and nontumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally, we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point toward the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits.
Published: 2021

29. Conservation of Aging and Cancer Epigenetic Signatures across Human and Mouse

Author: Pérez, Raúl F, primary, Tejedor, Juan Ramón, additional, Santamarina-Ojeda, Pablo, additional, Martínez, Virginia López, additional, Urdinguio, Rocío G, additional, Villamañán, Lucía, additional, Candiota, Ana Paula, additional, Sarró, Noemí Vidal, additional, Barradas, Marta, additional, Fernandez-Marcos, Pablo Jose, additional, Serrano, Manuel, additional, Fernández, Agustín F, additional, and Fraga, Mario F, additional
Published: 2021
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30. A promoter DNA demethylation landscape of human hematopoietic differentiation

Author: Calvanese, Vincenzo, Fernández, Agustín F., Urdinguio, Rocío G., Suárez-Alvarez, Beatriz, Mangas, Cristina, Pérez-García, Vicente, Bueno, Clara, Montes, Rosa, Ramos-Mejía, Verónica, Martínez-Camblor, Pablo, Ferrero, Cecilia, Assenov, Yassen, Bock, Christoph, Menendez, Pablo, Carrera, Ana Clara, Lopez-Larrea, Carlos, and Fraga, Mario F.
Published: 2012
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31. The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA

Author: López de Silanes, Isabel, Gorospe, Myriam, Taniguchi, Hiroaki, Abdelmohsen, Kotb, Srikantan, Subramanya, Alaminos, Miguel, Berdasco, María, Urdinguio, Rocío G., Fraga, Mario F., Jacinto, Filipe V., and Esteller, Manel
Published: 2009

32. Epigenetic downregulation of TET3 reduces genome‐wide 5hmC levels and promotes glioblastoma tumorigenesis

Author: Carella, Antonella, primary, Tejedor, Juan R., additional, García, María G., additional, Urdinguio, Rocío G., additional, Bayón, Gustavo F., additional, Sierra, Marta, additional, López, Virginia, additional, García‐Toraño, Estela, additional, Santamarina‐Ojeda, Pablo, additional, Pérez, Raúl F., additional, Bigot, Timothée, additional, Mangas, Cristina, additional, Corte‐Torres, María D., additional, Sáenz‐de‐Santa‐María, Inés, additional, Mollejo, Manuela, additional, Meléndez, Bárbara, additional, Astudillo, Aurora, additional, Chiara, María D., additional, Fernández, Agustín F., additional, and Fraga, Mario F., additional
Published: 2019
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33. Corrigendum: H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

Author: Fernández, Agustín F., primary, Bayón, Gustavo F., additional, Urdinguio, Rocío G., additional, Toraño, Estela G., additional, García, María G., additional, Carella, Antonella, additional, Petrus-Reurer, Sandra, additional, Ferrero, Cecilia, additional, Martinez-Camblor, Pablo, additional, Cubillo, Isabel, additional, García-Castro, Javier, additional, Delgado-Calle, Jesús, additional, Pérez-Campo, Flor M., additional, Riancho, José A., additional, Bueno, Clara, additional, Menéndez, Pablo, additional, Mentink, Anouk, additional, Mareschi, Katia, additional, Claire, Fabian, additional, Fagnani, Corrado, additional, Medda, Emanuela, additional, Toccaceli, Virgilia, additional, Brescianini, Sonia, additional, Moran, Sebastián, additional, Esteller, Manel, additional, Stolzing, Alexandra, additional, de Boer, Jan, additional, Nisticò, Lorenza, additional, Stazi, Maria A., additional, and Fraga, Mario F., additional
Published: 2019
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34. Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Author: European Commission, Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Principado de Asturias, German Research Foundation, European Research Council, Asociación Española Contra el Cáncer, Fundación Fero, Fundación la Caixa, Josep Carreras Leukemia Foundation, Generalitat de Catalunya, Obra Social Cajastur, Urdinguio, Rocío G., López, Virginia, Bayón, Gustavo F., Díaz de la Guardia, Rafael, Sierra, Marta I., García-Toraño, Estela, Pérez, Raúl F., García, María G., Carella, Antonella, Pruneda, Patricia C., Prieto López, Cristina, Dmitrijeva, Marija, Santamarina-Ojeda, Pablo, Belmonte, Thalia, Mangas, Cristina, Diaconu, Elena, Ferrero, Cecilia, Tejedor, Juan Ramón, Fernández-Morera, Juan L., Bravo, Cristina, Bueno, Clara, Sanjuan-Pla, Alejandra, Rodríguez López, Ramón María, Suárez-Álvarez, Beatriz, López-Larrea, Carlos, Bernal, Teresa, Colado, Enrique, Balbín, Milagros, García-Suarez, Olivia, Chiara, María-Dolores, Sáenz-de-Santa-María, Inés, Rodríguez Hernández, Francisco José, Pando-Sandoval, Ana, Rodrigo, Luis, Santos, Laura, Salas, Ana, Vallejo-Díaz, Jesús, Carrera, Ana C., Rico, Daniel, Hernández-López, Inmaculada, Vayá, Amparo, Ricart, José M., Seto, Edward, Sima-Teruel, Núria, Vaquero, Alejandro, Valledor, Luis, Cañal, María Jesús, Pisano, David, Graña-Castro, Osvaldo, Thomas, Tim, Voss, Anne K., Menéndez, Pablo, Villar-Garea, Ana, Deutzmann, Rainer, Fernández, Agustín F., Fraga, Mario F., European Commission, Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Principado de Asturias, German Research Foundation, European Research Council, Asociación Española Contra el Cáncer, Fundación Fero, Fundación la Caixa, Josep Carreras Leukemia Foundation, Generalitat de Catalunya, Obra Social Cajastur, Urdinguio, Rocío G., López, Virginia, Bayón, Gustavo F., Díaz de la Guardia, Rafael, Sierra, Marta I., García-Toraño, Estela, Pérez, Raúl F., García, María G., Carella, Antonella, Pruneda, Patricia C., Prieto López, Cristina, Dmitrijeva, Marija, Santamarina-Ojeda, Pablo, Belmonte, Thalia, Mangas, Cristina, Diaconu, Elena, Ferrero, Cecilia, Tejedor, Juan Ramón, Fernández-Morera, Juan L., Bravo, Cristina, Bueno, Clara, Sanjuan-Pla, Alejandra, Rodríguez López, Ramón María, Suárez-Álvarez, Beatriz, López-Larrea, Carlos, Bernal, Teresa, Colado, Enrique, Balbín, Milagros, García-Suarez, Olivia, Chiara, María-Dolores, Sáenz-de-Santa-María, Inés, Rodríguez Hernández, Francisco José, Pando-Sandoval, Ana, Rodrigo, Luis, Santos, Laura, Salas, Ana, Vallejo-Díaz, Jesús, Carrera, Ana C., Rico, Daniel, Hernández-López, Inmaculada, Vayá, Amparo, Ricart, José M., Seto, Edward, Sima-Teruel, Núria, Vaquero, Alejandro, Valledor, Luis, Cañal, María Jesús, Pisano, David, Graña-Castro, Osvaldo, Thomas, Tim, Voss, Anne K., Menéndez, Pablo, Villar-Garea, Ana, Deutzmann, Rainer, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.
Published: 2019

35. Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis

Author: Instituto de Salud Carlos III, Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología, Principado de Asturias, Ministerio de Economía y Competitividad (España), Fundación Científica Asociación Española Contra el Cáncer, European Commission, Fundación Ramón Areces, Obra Social Cajastur, Chiara, María-Dolores [0000-0002-1112-1583], Fraga, Mario F. [0000-0001-8450-2603], Carella, Antonella, Tejedor, Juan Ramón, García, María G., Urdinguio, Rocío G., Bayón, Gustavo F., Sierra, Marta I., López, Virginia, García-Toraño, Estela, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Bigot, Timothée, Mangas, Cristina, Corte-Torres, M. Daniela, Sáenz-de-Santa-María, Inés, Mollejo, Manuela, Meléndez, Bárbara, Astudillo, Aurora, Chiara, María-Dolores, Fernández, Agustín F., Fraga, Mario F., Instituto de Salud Carlos III, Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología, Principado de Asturias, Ministerio de Economía y Competitividad (España), Fundación Científica Asociación Española Contra el Cáncer, European Commission, Fundación Ramón Areces, Obra Social Cajastur, Chiara, María-Dolores [0000-0002-1112-1583], Fraga, Mario F. [0000-0001-8450-2603], Carella, Antonella, Tejedor, Juan Ramón, García, María G., Urdinguio, Rocío G., Bayón, Gustavo F., Sierra, Marta I., López, Virginia, García-Toraño, Estela, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Bigot, Timothée, Mangas, Cristina, Corte-Torres, M. Daniela, Sáenz-de-Santa-María, Inés, Mollejo, Manuela, Meléndez, Bárbara, Astudillo, Aurora, Chiara, María-Dolores, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Loss of 5‐hydroxymethylcytosine (5hmC) has been associated with mutations of the ten–eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild‐type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome‐wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome‐wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome‐wide alteration of 5hmC.
Published: 2019

36. Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes

Author: Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Pérez, Raúl F., Santamarina-Ojeda, Pablo, Tejedor, Juan Ramón, Urdinguio, Rocío G., Álvarez-Pitti, Julio, Redon, Pau, Fernández, Agustín F., Fraga, Mario F., Lurbe, Empar, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Obra Social Cajastur, Pérez, Raúl F., Santamarina-Ojeda, Pablo, Tejedor, Juan Ramón, Urdinguio, Rocío G., Álvarez-Pitti, Julio, Redon, Pau, Fernández, Agustín F., Fraga, Mario F., and Lurbe, Empar
Abstract: [Background] Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies., [Methods] To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects., [Results] We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements., [Conclusions] These data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.
Published: 2019

37. Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation

Author: Tejedor, J Ramón, primary, Bueno, Clara, additional, Cobo, Isabel, additional, Bayón, Gustavo F, additional, Prieto, Cristina, additional, Mangas, Cristina, additional, Pérez, Raúl F, additional, Santamarina, Pablo, additional, Urdinguio, Rocío G, additional, Menéndez, Pablo, additional, Fraga, Mario F, additional, and Fernández, Agustín F, additional
Published: 2018
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38. Epigenetic dysregulation ofTET2in human glioblastoma

Author: García, María G., primary, Carella, Antonella, additional, Urdinguio, Rocío G., additional, Bayón, Gustavo F., additional, Lopez, Virginia, additional, Tejedor, Juan Ramón, additional, Sierra, Marta I., additional, García-Toraño, Estela, additional, Santamarina, Pablo, additional, Perez, Raúl F., additional, Mangas, Cristina, additional, Astudillo, Aurora, additional, Corte-Torres, M. Daniela, additional, Sáenz-de-Santa-María, Inés, additional, Chiara, María-Dolores, additional, Fernández, Agustín F., additional, and Fraga, Mario F., additional
Published: 2018
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39. Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Author: European Commission, Urdinguio, Rocío G., López, Virginia, Bayón, Gustavo F., Díaz de la Guardia, Rafael, Sierra, Marta I., García-Toraño, Estela, Pérez, Raúl F., García, María G., Carella, Antonella, Pruneda, Patricia C., Prieto López, Cristina, Dmitrijeva, Marija, Santamarina-Ojeda, Pablo, Belmonte, Thalia, Mangas, Cristina, Diaconu, Elena, Ferrero, Cecilia, Tejedor, Juan Ramón, Fernández-Morera, Juan L., Bravo, Cristina, Bueno, Clara, Sanjuan-Pla, Alejandra, Rodríguez López, Ramón María, Suárez-Álvarez, Beatriz, López-Larrea, Carlos, Bernal, Teresa, Colado, Enrique, Balbín, Milagros, García-Suarez, Olivia, Chiara, María-Dolores, Sáenz-de-Santa-María, Inés, Rodríguez Hernández, Francisco José, Pando-Sandoval, Ana, Rodrigo, Luis, Santos, Laura, Salas, Ana, Vallejo-Díaz, Jesús, Carrera, Ana C., Rico, Daniel, Hernández-López, Inmaculada, Vayá, Amparo, Ricart, José M., Seto, Edward, Sima-Teruel, Núria, Vaquero, Alejandro, Valledor, Luis, Cañal, María Jesús, Pisano, David, Graña-Castro, Osvaldo, Thomas, Tim, Voss, Anne K., Menéndez, Pablo, Villar-Garea, Ana, Deutzmann, Rainer, Fernández, Agustín F., Fraga, Mario F., European Commission, Urdinguio, Rocío G., López, Virginia, Bayón, Gustavo F., Díaz de la Guardia, Rafael, Sierra, Marta I., García-Toraño, Estela, Pérez, Raúl F., García, María G., Carella, Antonella, Pruneda, Patricia C., Prieto López, Cristina, Dmitrijeva, Marija, Santamarina-Ojeda, Pablo, Belmonte, Thalia, Mangas, Cristina, Diaconu, Elena, Ferrero, Cecilia, Tejedor, Juan Ramón, Fernández-Morera, Juan L., Bravo, Cristina, Bueno, Clara, Sanjuan-Pla, Alejandra, Rodríguez López, Ramón María, Suárez-Álvarez, Beatriz, López-Larrea, Carlos, Bernal, Teresa, Colado, Enrique, Balbín, Milagros, García-Suarez, Olivia, Chiara, María-Dolores, Sáenz-de-Santa-María, Inés, Rodríguez Hernández, Francisco José, Pando-Sandoval, Ana, Rodrigo, Luis, Santos, Laura, Salas, Ana, Vallejo-Díaz, Jesús, Carrera, Ana C., Rico, Daniel, Hernández-López, Inmaculada, Vayá, Amparo, Ricart, José M., Seto, Edward, Sima-Teruel, Núria, Vaquero, Alejandro, Valledor, Luis, Cañal, María Jesús, Pisano, David, Graña-Castro, Osvaldo, Thomas, Tim, Voss, Anne K., Menéndez, Pablo, Villar-Garea, Ana, Deutzmann, Rainer, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.
Published: 2018

40. Epigenetic dysregulation of TET2 in human glioblastoma

Author: Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, Ministerio de Economía y Competitividad (España), European Commission, Obra Social Cajastur, Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología, García, María G., Carella, Antonella, Urdinguio, Rocío G., Bayón, Gustavo F., López, Virginia, Tejedor, Juan Ramón, Sierra, Marta I., García-Toraño, Estela, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Mangas, Cristina, Astudillo, Aurora, Corte-Torres, M. Daniela, Sáenz-de-Santa-María, Inés, Chiara, María-Dolores, Fernández, Agustín F., Fraga, Mario F., Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, Ministerio de Economía y Competitividad (España), European Commission, Obra Social Cajastur, Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología, García, María G., Carella, Antonella, Urdinguio, Rocío G., Bayón, Gustavo F., López, Virginia, Tejedor, Juan Ramón, Sierra, Marta I., García-Toraño, Estela, Santamarina-Ojeda, Pablo, Pérez, Raúl F., Mangas, Cristina, Astudillo, Aurora, Corte-Torres, M. Daniela, Sáenz-de-Santa-María, Inés, Chiara, María-Dolores, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma.
Published: 2018

41. Deregulation of the imprinted DLK1-DIO3 locus ncRNAs is associated with replicative senescence of human adipose-derived stem cells

Author: European Commission, Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, Comunidad de Madrid, García-López, Silvia, Albo-Castellanos, Carmen, Urdinguio, Rocío G., Cañón, Susana, Sánchez-Cabo, Fátima, Martínez-Serrano, Alberto, Fraga, Mario F., Bernard, Antonio, European Commission, Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, Comunidad de Madrid, García-López, Silvia, Albo-Castellanos, Carmen, Urdinguio, Rocío G., Cañón, Susana, Sánchez-Cabo, Fátima, Martínez-Serrano, Alberto, Fraga, Mario F., and Bernard, Antonio
Abstract: Background Human adult adipose-derived stem cells (hADSCs) have become the most promising cell source for regenerative medicine. However the prolonged ex vivo expansion periods required to obtain the necessary therapeutic dose promotes progressive senescence, with the concomitant reduction of their therapeutic potential. Aim and scope A better understanding of the determinants of hADSC senescence is needed to improve biosafety while preserving therapeutic efficiency. Here, we investigated the association between deregulation of the imprinted DLK1-DIO3 region and replicative senescence in hADSC cultures. Methods We compared hADSC cultures at short (P) and prolonged (P) passages, both in standard and low [O] (21 and 3%, respectively), in relation to replicative senescence. hADSCs were evaluated for expression alterations in the DLK1-DIO3 region on chromosome 14q32, and particularly in its main miRNA cluster. Results Comparison of hADSCs cultured at P or P surprisingly showed a quite significant fraction (69%) of upregulated miRNAs in P cultures mapping to the imprinted 14q32 locus, the largest miRNA cluster described in the genome. In agreement, expression of the lncRNA MEG3 (Maternally Expressed 3; Meg3/Gtl2), cultured at 21 and 3% [O], was also significantly higher in P than in P passages. During hADSC replicative senescence the AcK16H4 activating mark was found to be significantly associated with the deregulation of the entire DLK1-DIO3 locus, with a secondary regulatory role for the methylation of DMR regions. Conclusion A direct relationship between DLK1-DIO3 deregulation and replicative senescence of hADSCs is reported, involving upregulation of a very significant fraction of its largest miRNA cluster (14q32.31), paralleled by the progressive overexpression of the lncRNA MEG3, which plays a central role in the regulation of Dlk1/Dio3 activation status in mice.
Published: 2018

42. 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, María, Bergmann, Anke K., Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M., Diep, Dinh, Fernández, Agustín F., Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Kläver, Ruth, Kreutz, Martin, Kulis, Marta, López, Virginia, Nair, Shalima S., Paul, Dirk S., Plongthongkum, Nongluk, Qu, Wenjia, Queirós, Ana C., Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocío G., Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J., Beck, Stephan, Clark, Susan J., Esteller, Manel, Ferguson-Smith, Anne C., Fraga, Mario F., Guldberg, Per, Lotte Hansen, Lise, Laird, Peter W., Martín, José Ignacio, Nygren, Anders O. H., Peist, Ralf, Plass, Christoph, Shames, David S., Siebert, Reiner, Sun, Xueguang, Tost, Jörg, Walter, Jörn, Zhang, Kun, Biotechnology and Biological Sciences Research Council (UK), Federal Ministry of Education and Research (Germany), National Institute on Mental Health (US), European Commission, Deutsches Krebsforschungszentrum, and Universitat de Barcelona
Subjects: 0301 basic medicine, Genetic Markers, BLUEPRINT consortium, ADN, MathematicsofComputing_GENERAL, Biomedical Engineering, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Bioengineering, Computational biology, Biology, Bioinformatics, Applied Microbiology and Biotechnology, Sensitivity and Specificity, 03 medical and health sciences, InformationSystems_MODELSANDPRINCIPLES, Diagnòstic, MD Multidisciplinary, Diagnosis, Promoter Regions, Genetic, DNA Modification Methylases, ComputingMilieux_THECOMPUTINGPROFESSION, Biochemical markers, TheoryofComputation_GENERAL, High-Throughput Nucleotide Sequencing, Reproducibility of Results, DNA, DNA Methylation, 3. Good health, High-Throughput Screening Assays, Biomarker, 030104 developmental biology, CpG site, Marcadors bioquímics, DNA methylation, Molecular Medicine, Algorithms, Biotechnology
Abstract: The BLUEPRINT consortium, 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., This work was performed in the context of the BLUEPRINT project (European Union’s Seventh Framework Programme grant agreement 282510), which funded the study logistics and the integrative data analysis. The assay costs were paid by the contributing laboratories using institutional funds and the following grants: BBSRC BB/G020930/1, BBSRC BB/G020930/1, BMBF 01KU1001A, BMBF 01KU1002A, BMBF 01KU1216F, EU-FP7 282510, FWF I 1575-B19, NHMRC 1063559, NHMRC 1088144 and the DKFZ Graduate School.
Published: 2015
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43. Epigenetic downregulation of TET3 reduces genome‐wide 5hmC levels and promotes glioblastoma tumorigenesis.

Author: Carella, Antonella, Tejedor, Juan R., García, María G., Urdinguio, Rocío G., Bayón, Gustavo F., Sierra, Marta, López, Virginia, García‐Toraño, Estela, Santamarina‐Ojeda, Pablo, Pérez, Raúl F., Bigot, Timothée, Mangas, Cristina, Corte‐Torres, María D., Sáenz‐de‐Santa‐María, Inés, Mollejo, Manuela, Meléndez, Bárbara, Astudillo, Aurora, Chiara, María D., Fernández, Agustín F., and Fraga, Mario F.
Subjects: EPIGENETICS, METHYLGUANINE, DOWNREGULATION, GENETIC regulation, CELL growth, EPIGENOMICS, CELL lines
Abstract: Loss of 5‐hydroxymethylcytosine (5hmC) has been associated with mutations of the ten–eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild‐type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome‐wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome‐wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome‐wide alteration of 5hmC. What's new? Reduced levels of 5‐hydroxymethylcytosine (5hmC), an epigenetic mark generated by TET enzymes, have been observed in multiple cancers. Although mutations in TET enzymes have been associated with 5hmC loss, other mechanisms may be at play. Here, the authors show that DNA hypermethylation, loss of DNA hydroxymethylation, and reduction of activating histone marks in the TET3 gene impair TET3 expression and lead to a genome‐wide reduction in 5hmC levels in glioma. Important protease inhibitor and TET3 downstream target gene RECK might help mediate tumorigenesis. The results suggest that epigenetic repression of TET3 promotes glioblastoma tumorigenesis through the genome‐wide alteration of 5hmC. [ABSTRACT FROM AUTHOR]
Published: 2020
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44. Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation

Author: European Commission, Tejedor, Juan Ramón [0000-0002-4061-9698], Bayón, Gustavo F. [0000-0002-0763-0473], Pérez, Raúl F. [0000-0003-4336-9898], Santamarina-Ojeda, Pablo [0000-0002-7439-8467], Menéndez, Pablo [0000-0001-9372-1007], Fraga, Mario F. [0000-0001-8450-2603], Fernández, Agustín F. [0000-0002-3792-4085], Tejedor, Juan Ramón, Bueno, Clara, Cobo, Isabel, Bayón, Gustavo F., Prieto López, Cristina, Mangas, Cristina, Pérez, Raúl F., Santamarina-Ojeda, Pablo, Urdinguio, Rocío G., Menéndez, Pablo, Fraga, Mario F., Fernández, Agustín F., European Commission, Tejedor, Juan Ramón [0000-0002-4061-9698], Bayón, Gustavo F. [0000-0002-0763-0473], Pérez, Raúl F. [0000-0003-4336-9898], Santamarina-Ojeda, Pablo [0000-0002-7439-8467], Menéndez, Pablo [0000-0001-9372-1007], Fraga, Mario F. [0000-0001-8450-2603], Fernández, Agustín F. [0000-0002-3792-4085], Tejedor, Juan Ramón, Bueno, Clara, Cobo, Isabel, Bayón, Gustavo F., Prieto López, Cristina, Mangas, Cristina, Pérez, Raúl F., Santamarina-Ojeda, Pablo, Urdinguio, Rocío G., Menéndez, Pablo, Fraga, Mario F., and Fernández, Agustín F.
Abstract: Epigenetic regulation plays an important role in cellular development and differentiation. A detailed map of the DNA methylation dynamics that occur during cell differentiation would contribute to decipher the molecular networks governing cell fate commitment. In this study we used the most recent Illumina MethylationEPIC Beadchip platform to describe the genome-wide DNA methylation changes observed throughout hematopoietic maturation by analyzing multiple hematopoietic cell types at different developmental stages.
Published: 2017

45. DNA methylation changes in human lung epithelia cells exposed to multi-walled carbon nanotubes

Author: European Commission, Obra Social Cajastur, Instituto de Salud Carlos III, Instituto Universitario de Oncología del Principado de Asturias, Sierra, Marta I., Rubio, Laura, Bayón, Gustavo F., Cobo, Isabel, Menéndez, Pablo, Morales, Paula, Mangas, Cristina, Urdinguio, Rocío G., López, Virginia, Fernández, Adolfo, Vales, Gerard, Marcos, Ricard, Torrecillas, Ramón, Fernández, Agustín F., Fraga, Mario F., European Commission, Obra Social Cajastur, Instituto de Salud Carlos III, Instituto Universitario de Oncología del Principado de Asturias, Sierra, Marta I., Rubio, Laura, Bayón, Gustavo F., Cobo, Isabel, Menéndez, Pablo, Morales, Paula, Mangas, Cristina, Urdinguio, Rocío G., López, Virginia, Fernández, Adolfo, Vales, Gerard, Marcos, Ricard, Torrecillas, Ramón, Fernández, Agustín F., and Fraga, Mario F.
Abstract: Humans are increasingly exposed to nanoparticles and, although many of their physiological effects have been described, the molecular mechanisms underlying them are still largely unknown. The present study aimed to determine the possible role of certain epigenetic mechanisms in the cellular response of human lung epithelial cells that are triggered by long-term exposure to titanium dioxide nanoparticles (TiONPs) and multi-walled carbon nanotubes (MWCNTs). The results showed that exposure to TiONPs had only minor effects on genome-wide DNA methylation. However, we identified 755 CpG sites showing consistent DNA hypomethylation in cells exposed to MWCNTs. These sites were mainly located at low density CpG regions and enhancers, and very frequently on the X chromosome. Our results thus suggest that long-term MWCNT exposure may have important effects on the epigenome.
Published: 2017

46. Chapter 8 - Epigenetics, Inflammation, and Aging

Author: Urdinguio, Rocio G., Rodriguez-Rodero, Sandra, Fernandez, Agustin F., and Fraga, Mario F.
Published: 2014
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47. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications

Author: Biotechnology and Biological Sciences Research Council (UK), Federal Ministry of Education and Research (Germany), National Institute of Mental Health (US), European Commission, Deutsches Krebsforschungszentrum, Bock, Christoph, Halbritter, Florian, Carmona, Francisco J., Tierling, Sascha, Datlinger, Paul, Assenov, Yassen, Berdasco, María, Bergmann, Anke K., Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M., Diep, Dinh, Fernández, Agustín F., Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Kläver, Ruth, Kreutz, Martin, Kulis, Marta, López, Virginia, Nair, Shalima S., Paul, Dirk S., Plongthongkum, Nongluk, Qu, Wenjia, Queirós, Ana C., Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocío G., Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J., Beck, Stephan, Clark, Susan J., Esteller, Manel, Ferguson-Smith, Anne C., Fraga, Mario F., Guldberg, Per, Lotte Hansen, Lise, Laird, Peter W., Martín, José Ignacio, Nygren, Anders O. H., Peist, Ralf, Plass, Christoph, Shames, David S., Siebert, Reiner, Sun, Xueguang, Tost, Jörg, Walter, Jörn, Zhang, Kun, Biotechnology and Biological Sciences Research Council (UK), Federal Ministry of Education and Research (Germany), National Institute of Mental Health (US), European Commission, Deutsches Krebsforschungszentrum, Bock, Christoph, Halbritter, Florian, Carmona, Francisco J., Tierling, Sascha, Datlinger, Paul, Assenov, Yassen, Berdasco, María, Bergmann, Anke K., Booher, Keith, Busato, Florence, Campan, Mihaela, Dahl, Christina, Dahmcke, Christina M., Diep, Dinh, Fernández, Agustín F., Gerhauser, Clarissa, Haake, Andrea, Heilmann, Katharina, Holcomb, Thomas, Hussmann, Dianna, Ito, Mitsuteru, Kläver, Ruth, Kreutz, Martin, Kulis, Marta, López, Virginia, Nair, Shalima S., Paul, Dirk S., Plongthongkum, Nongluk, Qu, Wenjia, Queirós, Ana C., Reinicke, Frank, Sauter, Guido, Schlomm, Thorsten, Statham, Aaron, Stirzaker, Clare, Strogantsev, Ruslan, Urdinguio, Rocío G., Walter, Kimberly, Weichenhan, Dieter, Weisenberger, Daniel J., Beck, Stephan, Clark, Susan J., Esteller, Manel, Ferguson-Smith, Anne C., Fraga, Mario F., Guldberg, Per, Lotte Hansen, Lise, Laird, Peter W., Martín, José Ignacio, Nygren, Anders O. H., Peist, Ralf, Plass, Christoph, Shames, David S., Siebert, Reiner, Sun, Xueguang, Tost, Jörg, Walter, Jörn, and Zhang, Kun
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

48. Longitudinal study of DNA methylation during the first 5 years of life

Author: Fundación Ramón Areces, Obra Social Cajastur, Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, European Commission, Urdinguio, Rocío G., Torró, María Isabel, Bayón, Gustavo F., Álvarez-Pitti, Julio, Fernández, Agustín F., Redon, Pau, Fraga, Mario F., Lurbe, Empar, Fundación Ramón Areces, Obra Social Cajastur, Instituto de Salud Carlos III, Fundación Científica Asociación Española Contra el Cáncer, European Commission, Urdinguio, Rocío G., Torró, María Isabel, Bayón, Gustavo F., Álvarez-Pitti, Julio, Fernández, Agustín F., Redon, Pau, Fraga, Mario F., and Lurbe, Empar
Abstract: [Background]: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. [Methods]: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. [Results]: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. [Conclusions]: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention.
Published: 2016

49. Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells

Author: Instituto de Salud Carlos III, Fundación Ramón Areces, Principado de Asturias, Comunidad de Madrid, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Obra Social Cajastur, Toraño, Estela G., Bayón, Gustavo F., Real, Álvaro del, Sierra, Marta I., García, María G., Carella, Antonella, Belmonte, Thalia, Urdinguio, Rocío G., Cubillo, Isabel, García-Castro, Javier, Delgado-Calle, Jesús, Pérez-Campo, Flor Maria, Riancho, José A., Fraga, Mario F., Fernández, Agustín F., Instituto de Salud Carlos III, Fundación Ramón Areces, Principado de Asturias, Comunidad de Madrid, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Obra Social Cajastur, Toraño, Estela G., Bayón, Gustavo F., Real, Álvaro del, Sierra, Marta I., García, María G., Carella, Antonella, Belmonte, Thalia, Urdinguio, Rocío G., Cubillo, Isabel, García-Castro, Javier, Delgado-Calle, Jesús, Pérez-Campo, Flor Maria, Riancho, José A., Fraga, Mario F., and Fernández, Agustín F.
Abstract: [Background]: Age-associated changes in genomic DNA methylation have been primarily attributed to 5-methylcytosine (5mC). However, the recent discovery of 5-hydroxymethylcytosine (5hmC) suggests that this epigenetic mark might also play a role in the process. [Methods]: Here, we analyzed the genome-wide profile of 5hmc in mesenchymal stem cells (MSCs) obtained from bone-marrow donors, aged 2-89 years. [Results]: We identified 10,685 frequently hydroxymethylated CpG sites in MSCs that were, as in other cell types, significantly associated with low density CpG regions, introns, the histone posttranslational modification H3k4me1 and enhancers. Study of the age-associated changes to 5hmC identified 785 hyper- and 846 hypo-hydroxymethylated CpG sites in the MSCs obtained from older individuals. [Conclusions]: DNA hyper-hydroxymethylation in the advanced-age group was associated with loss of 5mC, which suggests that, at specific CpG sites, this epigenetic modification might play a role in DNA methylation changes during lifetime. Since bone-marrow MSCs have many clinical applications, and the fact that the epigenomic alterations in this cell type associated with aging identified in this study could have associated functional effects, the age of donors should be taken into account in clinical settings.
Published: 2016

50. Age-associated hydroxymethylation in human bone-marrow mesenchymal stem cells

Author: Toraño, Estela G., primary, Bayón, Gustavo F., additional, del Real, Álvaro, additional, Sierra, Marta I., additional, García, María G., additional, Carella, Antonella, additional, Belmonte, Thalia, additional, Urdinguio, Rocío G., additional, Cubillo, Isabel, additional, García-Castro, Javier, additional, Delgado-Calle, Jesús, additional, Pérez-Campo, Flor M., additional, Riancho, José A., additional, Fraga, Mario F., additional, and Fernández, Agustín F., additional
Published: 2016
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