Biochemistry, Genetics and Molecular Biology, Computer Science Applications
34
Scopus Publications
Scopus Publications
Double vulnerability of active-NRF2 lung squamous cell carcinoma to NRF2 and TRIM24 Miriam Sánchez-Ortega, Antonio Garrido, Lorena Sanz, Rafael Torres-Pérez, Carmen Hernandez, Alvaro Gutierrez-Uzquiza, Ming Sound Tsao, Ana Clara Carrera Molecular Cancer, 2025 Lung squamous cell cancer (LUSC) is associated with very poor survival due to the lack of specific treatments. A common genetic alteration in LUSC involves mutations in NFE2L2 (protein named NRF2) or its regulator, KEAP1 , resulting in increased activity of the NRF2 transcription factor (TF). This study compares the requirement for active-NRF2 in LUSC cell lines. Although normal-NRF2 cells are more sensitive to oxidative stress, they do not require NRF2 for survival under non-stress conditions, in contrast, LUSC cells with active-NRF2 mutations depend on NRF2 for viability. NRF2 depletion in patient-derived organoid cultures with active-NRF2 as well as in xenografts with active-NRF2 triggers cell death. The focus of this study is to find genes that rescue cell death upon NRF2-depletion in active-NRF2 cells. A CRISPRa/dCas9 screening for gene targets capable of rescuing cell survival in these cells identified TRIM24 as a gene whose expression saves cell survival in NRF2-depleted active-NRF2 LUSC cells. Alongside oxidative stress, the lack of TRIM24 selectively contributed to the induction of cell death (apoptosis and ferroptosis) in active-NRF2 LUSC cells. Cells with a high NFE2L2/KEAP1 copy number ratio also undergo cell death. The increase in cell death observed upon TRIM24 depletion involves a reduction of TRIM24/PI3Kα complexes which destabilizes the PI3Kα catalytic subunit. Notably, overexpression of PI3Kα rescues cell survival in TRIM24-depleted active-NRF2 cells. These findings point to novel therapeutic approaches in LUSC.
Genome resequencing and custom genotyping elucidates the origin and dissemination history of an emblematic grapevine cultivar, ‘Tempranillo Tinto’ Javier Tello, Pablo Carbonell-Bejerano, Rafael Torres-Pérez, Yolanda Ferradás, Carolina Royo, Javier Portu, José Félix Cibriáin, Juan Carlos Oliveros, Javier Ibáñez, José Miguel Martínez-Zapater Horticulture Research, 2025 Grapevine cultivars are vegetatively propagated to maintain their varietal characteristics. However, long periods of cultivar multiplication result in the accumulation of spontaneous somatic mutations that can differ among clonal lines. Here, we explored this intravarietal genetic diversity to trace back the origin and dissemination history of ‘Tempranillo Tinto’, the third most cultivated wine grape variety worldwide. A stringent somatic variant calling over whole-genome resequencing data of 35 ‘Tempranillo Tinto’ grapevines from seven Iberian winemaking regions revealed 158 somatic single nucleotide variants (SNVs) shared by some of the plants. Among them, 56 highly informative SNVs were used to custom-design a high-throughput intravarietal genotyping assay, which was validated and used to analyze 185 vines representing a broader geographic distribution. Phylogenetic analyses revealed three major clonal lineages in ‘Tempranillo Tinto’ that grouped the samples according to their geographic origin. By inferring the ancestral SNV alleles in ‘Tempranillo Tinto’ from whole-genome resequencing data of its parents, we determined the Ebro River Valley in Northeast Spain as the most likely birthplace of the cultivar. Derived alleles revealed one major historical human-mediated westward dissemination route from this original site towards the winemaking regions following the Duero River Valley and then, to the South in Portugal. Clonal lineages also revealed the polyphyletic nature of somatic variant traits of interest for grape and wine quality production under climate change conditions. Our findings elucidate the origin and historical dispersal of ‘Tempranillo Tinto’ and underscore genomic strategies for advancing clonal improvement to ensure the sustainability of valuable traditional grapevine cultivars.
The trichome pattern diversity of Cardamine shares genetic mechanisms with Arabidopsis but differs in environmental drivers Alberto Fuster-Pons, Alba Murillo-Sánchez, Belén Méndez-Vigo, Arnald Marcer, Bjorn Pieper, Rafael Torres-Pérez, Juan Carlos Oliveros, Miltos Tsiantis, F Xavier Picó, Carlos Alonso-Blanco Plant Physiology, 2024 Natural variation in trichome pattern (amount and distribution) is prominent among populations of many angiosperms. However, the degree of parallelism in the genetic mechanisms underlying this diversity and its environmental drivers in different species remain unclear. To address these questions, we analyzed the genomic and environmental bases of leaf trichome pattern diversity in Cardamine hirsuta, a relative of Arabidopsis (Arabidopsis thaliana). We characterized 123 wild accessions for their genomic diversity, leaf trichome patterns at different temperatures, and environmental adjustments. Nucleotide diversities and biogeographical distribution models identified two major genetic lineages with distinct demographic and adaptive histories. Additionally, C. hirsuta showed substantial variation in trichome pattern and plasticity to temperature. Trichome amount in C. hirsuta correlated positively with spring precipitation but negatively with temperature, which is opposite to climatic patterns in A. thaliana. Contrastingly, genetic analysis of C. hirsuta glabrous accessions indicated that, like for A. thaliana, glabrousness is caused by null mutations in ChGLABRA1 (ChGL1). Phenotypic genome-wide association studies (GWAS) further identified a ChGL1 haplogroup associated with low trichome density and ChGL1 expression. Therefore, a ChGL1 series of null and partial loss-of-function alleles accounts for the parallel evolution of leaf trichome pattern in C. hirsuta and A. thaliana. Finally, GWAS also detected other candidate genes (e.g. ChETC3, ChCLE17) that might affect trichome pattern. Accordingly, the evolution of this trait in C. hirsuta and A. thaliana shows partially conserved genetic mechanisms but is likely involved in adaptation to different environments.
Variation and plasticity in life-history traits and fitness of wild Arabidopsis thaliana populations are not related to their genotypic and ecological diversity Raul de la Mata, Almudena Mollá-Morales, Belén Méndez-Vigo, Rafael Torres-Pérez, Juan Carlos Oliveros, Rocío Gómez, Arnald Marcer, Antonio R. Castilla, Magnus Nordborg, Carlos Alonso-Blanco, F. Xavier Picó BMC Ecology and Evolution, 2024 Background Despite its implications for population dynamics and evolution, the relationship between genetic and phenotypic variation in wild populations remains unclear. Here, we estimated variation and plasticity in life-history traits and fitness of the annual plant Arabidopsis thaliana in two common garden experiments that differed in environmental conditions. We used up to 306 maternal inbred lines from six Iberian populations characterized by low and high genotypic (based on whole-genome sequences) and ecological (vegetation type) diversity. Results Low and high genotypic and ecological diversity was found in edge and core Iberian environments, respectively. Given that selection is expected to be stronger in edge environments and that ecological diversity may enhance both phenotypic variation and plasticity, we expected genotypic diversity to be positively associated with phenotypic variation and plasticity. However, maternal lines, irrespective of the genotypic and ecological diversity of their population of origin, exhibited a substantial amount of phenotypic variation and plasticity for all traits. Furthermore, all populations harbored maternal lines with canalization (robustness) or sensitivity in response to harsher environmental conditions in one of the two experiments. Conclusions Overall, we conclude that the environmental attributes of each population probably determine their genotypic diversity, but all populations maintain substantial phenotypic variation and plasticity for all traits, which represents an asset to endure in changing environments.
Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma Bruna Calsina, Elena Piñeiro-Yáñez, Ángel M. Martínez-Montes, Eduardo Caleiras, Ángel Fernández-Sanromán, María Monteagudo, Rafael Torres-Pérez, Coral Fustero-Torre, Marta Pulgarín-Alfaro, Eduardo Gil, Rocío Letón, Scherezade Jiménez, Santiago García-Martín, Maria Carmen Martin, Juan María Roldán-Romero, Javier Lanillos, Sara Mellid, María Santos, Alberto Díaz-Talavera, Ángeles Rubio, Patricia González, Barbara Hernando, Nicole Bechmann, Margo Dona, María Calatayud, Sonsoles Guadalix, Cristina Álvarez-Escolá, Rita M. Regojo, Javier Aller, Maria Isabel Del Olmo-Garcia, Adrià López-Fernández, Stephanie M. J. Fliedner, Elena Rapizzi, Martin Fassnacht, Felix Beuschlein, Marcus Quinkler, Rodrigo A. Toledo, Massimo Mannelli, Henri J. Timmers, Graeme Eisenhofer, Sandra Rodríguez-Perales, Orlando Domínguez, Geoffrey Macintyre, Maria Currás-Freixes, Cristina Rodríguez-Antona, Alberto Cascón, Luis J. Leandro-García, Cristina Montero-Conde, Giovanna Roncador, Juan Fernando García-García, Karel Pacak, Fátima Al-Shahrour, Mercedes Robledo Nature Communications, 2023 The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
Selective Pressure by Rifampicin Modulates Mutation Rates and Evolutionary Trajectories of Mycobacterial Genomes E. Cebrián-Sastre, A. Chiner-Oms, R. Torres-Pérez, I. Comas, J. C. Oliveros, J. Blázquez, A. Castañeda-García Microbiology Spectrum, 2023 Rifampicin is the most important first-line antibiotic against mycobacterial infections, including tuberculosis, one of the top causes of death worldwide. Acquisition of rifampicin resistance constitutes a major global public health problem that makes the control of the disease challenging.
Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution Estel Ramos‐Marquès, Laura García‐Mendívil, María Pérez‐Zabalza, Hazel Santander‐Badules, Sabarathinam Srinivasan, Juan Carlos Oliveros, Rafael Torres‐Pérez, Alberto Cebollada, José María Vallejo‐Gil, Pedro Carlos Fresneda‐Roldán, Javier Fañanás‐Mastral, Manuel Vázquez‐Sancho, Marta Matamala‐Adell, Juan Fernando Sorribas‐Berjón, Javier André Bellido‑Morales, Francisco Javier Mancebón‑Sierra, Alexánder Sebastián Vaca‑Núñez, Carlos Ballester‐Cuenca, Manuel Jiménez‐Navarro, José Manuel Villaescusa, Elisa Garrido‐Huéscar, Margarita Segovia‐Roldán, Aida Oliván‐Viguera, Carlos Gómez‐González, Gorka Muñiz, Emiliano Diez, Laura Ordovás, Esther Pueyo Aging Cell, 2021 Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA‐associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA‐based analyses uncover depleted cardiac‐specific processes, among other relevant functions, that are undetected by CA. Twenty BA‐related microRNAs are identified, and two of them highly heart‐enriched that are present in plasma. We describe a microRNA‐gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research.
Genetic variation and association analyses identify genes linked to fruit set-related traits in grapevine Lalla Hasna Zinelabidine, Rafael Torres-Pérez, Jérôme Grimplet, Elisa Baroja, Sergio Ibáñez, Pablo Carbonell-Bejerano, José Miguel Martínez-Zapater, Javier Ibáñez, Javier Tello Plant Science, 2021 Grapevine is one of the most valuable fruit crops in the world. Adverse environmental conditions reduce fruit quality and crop yield, so understanding the genetic and molecular mechanisms determining crop yield components is essential to optimize grape production. The analysis of a diverse collection of grapevine cultivars allowed us to evaluate the relationship between fruit set-related components of yield, including the incidence of reproductive disorders such as coulure and millerandage. The collection displayed a great phenotypic variation that we surveyed in a genetics association study using 15,309 single nucleotide polymorphisms (SNPs) detected in the sequence of 289 candidate genes scattered across the 19 grapevine linkage groups. After correcting statistical models for population structure and linkage disequilibrium effects, 164 SNPs from 34 of these genes were found to associate with fruit set-related traits, supporting a complex polygenic determinism. Many of them were found in the sequence of different putative MADS-box transcription factors, a gene family related with plant reproductive development control. In addition, we observed an additive effect of some of the associated SNPs on the phenotype, suggesting that advantageous alleles from different loci could be pyramided to generate superior cultivars with optimized fruit production.
MYB transcription factors drive evolutionary innovations in Arabidopsis fruit trichome patterning Noelia Arteaga, Marija Savic, Belén Méndez-Vigo, Alberto Fuster-Pons, Rafael Torres-Pérez, Juan Carlos Oliveros, F Xavier Picó, Carlos Alonso-Blanco Plant Cell, 2021 Both inter- and intra-specific diversity has been described for trichome patterning in fruits, which is presumably involved in plant adaptation. However, the mechanisms underlying this developmental trait have been hardly addressed. Here we examined natural populations of Arabidopsis (Arabidopsis thaliana) that develop trichomes in fruits and pedicels, phenotypes previously not reported in the Arabidopsis genus. Genetic analyses identified five loci, MALAMBRUNO 1–5 (MAU1–5), with MAU2, MAU3, and MAU5 showing strong epistatic interactions that are necessary and sufficient to display these traits. Functional characterization of these three loci revealed cis-regulatory mutations in TRICHOMELESS1 and TRIPTYCHON, as well as a structural mutation in GLABRA1. Therefore, the multiple mechanisms controlled by three MYB transcription factors of the core regulatory network for trichome patterning have jointly been modulated to trigger trichome development in fruits. Furthermore, analyses of worldwide accessions showed that these traits and mutations only occur in a highly differentiated relict lineage from the Iberian Peninsula. In addition, these traits and alleles were associated with low spring precipitation, which suggests that trichome development in fruits and pedicels might be involved in climatic adaptation. Thus, we show that the combination of synergistic mutations in a gene regulatory circuit has driven evolutionary innovations in fruit trichome patterning in Arabidopsis.
Hsa-miR-139-5p is a prognostic thyroid cancer marker involved in HNRNPF-mediated alternative splicing Cristina Montero‐Conde, Osvaldo Graña‐Castro, Guillermo Martín‐Serrano, Ángel M. Martínez‐Montes, Eduardo Zarzuela, Javier Muñoz, Rafael Torres‐Perez, Guillermo Pita, Alfonso Cordero‐Barreal, Luis J. Leandro‐García, Rocío Letón, Isabel López de Silanes, Sonsoles Guadalix, Andrés Pérez‐Barrios, Federico Hawkins, Almudena Guerrero‐Álvarez, Cristina Álvarez‐Escolá, Rita M. Regojo‐Zapata, Bruna Calsina, Laura Remacha, Juan M. Roldán‐Romero, María Santos, Javier Lanillos, Mireia Jordá, Garcilaso Riesco‐Eizaguirre, Carles Zafon, Anna González‐Neira, Maria A. Blasco, Fátima Al‐Shahrour, Cristina Rodríguez‐Antona, Alberto Cascón, Mercedes Robledo International Journal of Cancer, 2020
Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas Laura Remacha, David Pirman, Christopher E. Mahoney, Javier Coloma, Bruna Calsina, Maria Currás-Freixes, Rocío Letón, Rafael Torres-Pérez, Susan Richter, Guillermo Pita, Belén Herráez, Giovanni Cianchetta, Emiliano Honrado, Lorena Maestre, Miguel Urioste, Javier Aller, Óscar García-Uriarte, María Ángeles Gálvez, Raúl M. Luque, Marcos Lahera, Cristina Moreno-Rengel, Graeme Eisenhofer, Cristina Montero-Conde, Cristina Rodríguez-Antona, Óscar Llorca, Gromoslaw A. Smolen, Mercedes Robledo, Alberto Cascón American Journal of Human Genetics, 2019
Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma Bruna Calsina, Luis Jaime Castro-Vega, Rafael Torres-Pérez, Lucía Inglada-Pérez, Maria Currás-Freixes, Juan María Roldán-Romero, Veronika Mancikova, Rocío Letón, Laura Remacha, María Santos, Nelly Burnichon, Charlotte Lussey-Lepoutre, Elena Rapizzi, Osvaldo Graña, Cristina Álvarez-Escolá, Aguirre A de Cubas, Javier Lanillos, Alfonso Cordero-Barreal, Ángel M Martínez-Montes, Alexandre Bellucci, Laurence Amar, Fabio Luiz Fernandes-Rosa, María Calatayud, Javier Aller, Cristina Lamas, Júlia Sastre-Marcos, Letizia Canu, Esther Korpershoek, Henri J Timmers, Jacques WM Lenders, Felix Beuschlein, Martin Fassnacht-Capeller, Graeme Eisenhofer, Massimo Mannelli, Fátima Al-Shahrour, Judith Favier, Cristina Rodríguez-Antona, Alberto Cascón, Cristina Montero-Conde, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo Theranostics, 2019
Gain-of-function mutations in DNMT3A in patients with paraganglioma Laura Remacha, Maria Currás-Freixes, Raúl Torres-Ruiz, Francesca Schiavi, Rafael Torres-Pérez, Bruna Calsina, Rocío Letón, Iñaki Comino-Méndez, Juan M Roldán-Romero, Cristina Montero-Conde, María Santos, Lucía Inglada Pérez, Guillermo Pita, María R. Alonso, Emiliano Honrado, Susana Pedrinaci, Benedicto Crespo-Facorro, Antonio Percesepe, Maurizio Falcioni, Sandra Rodríguez-Perales, Esther Korpershoek, Santiago Ramón-Maiques, Giuseppe Opocher, Cristina Rodríguez-Antona, Mercedes Robledo, Alberto Cascón Genetics in Medicine, 2018
PheoSeq: A Targeted Next-Generation Sequencing Assay for Pheochromocytoma and Paraganglioma Diagnostics Maria Currás-Freixes, Elena Piñeiro-Yañez, Cristina Montero-Conde, María Apellániz-Ruiz, Bruna Calsina, Veronika Mancikova, Laura Remacha, Susan Richter, Tonino Ercolino, Natalie Rogowski-Lehmann, Timo Deutschbein, María Calatayud, Sonsoles Guadalix, Cristina Álvarez-Escolá, Cristina Lamas, Javier Aller, Julia Sastre-Marcos, Conxi Lázaro, Juan C. Galofré, Ana Patiño-García, Amparo Meoro-Avilés, Judith Balmaña-Gelpi, Paz De Miguel-Novoa, Milagros Balbín, Xavier Matías-Guiu, Rocío Letón, Lucía Inglada-Pérez, Rafael Torres-Pérez, Juan M. Roldán-Romero, Cristina Rodríguez-Antona, Stephanie M.J. Fliedner, Giuseppe Opocher, Karel Pacak, Esther Korpershoek, Ronald R. de Krijger, Laurent Vroonen, Massimo Mannelli, Martin Fassnacht, Felix Beuschlein, Graeme Eisenhofer, Alberto Cascón, Fátima Al-Shahrour, Mercedes Robledo Journal of Molecular Diagnostics, 2017
Overview of BioCreative II gene normalization Alexander A Morgan, Zhiyong Lu, Xinglong Wang, Aaron M Cohen, Juliane Fluck, Patrick Ruch, Anna Divoli, Katrin Fundel, Robert Leaman, Jörg Hakenberg, Chengjie Sun, Heng-hui Liu, Rafael Torres, Michael Krauthammer, William W Lau, Hongfang Liu, Chun-Nan Hsu, Martijn Schuemie, K Bretonnel Cohen, Lynette Hirschman Genome Biology, 2008
Overview of BioCreative II gene mention recognition Larry Smith, Lorraine K Tanabe, Rie Johnson nee Ando, Cheng-Ju Kuo, I-Fang Chung, Chun-Nan Hsu, Yu-Shi Lin, Roman Klinger, Christoph M Friedrich, Kuzman Ganchev, Manabu Torii, Hongfang Liu, Barry Haddow, Craig A Struble, Richard J Povinelli, Andreas Vlachos, William A Baumgartner, Lawrence Hunter, Bob Carpenter, Richard Tzong-Han Tsai, Hong-Jie Dai, Feng Liu, Yifei Chen, Chengjie Sun, Sophia Katrenko, Pieter Adriaans, Christian Blaschke, Rafael Torres, Mariana Neves, Preslav Nakov, Anna Divoli, Manuel Maña-López, Jacinto Mata, W John Wilbur Genome Biology, 2008
