Ezponda, T. (Teresa)
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- Development of a novel splice array platform and its application in the identification of alternative splice variants in lung cancer(BioMed Central, 2010-06-03) Pajares, M.J. (María José); Anton, M.A. (Miguel Ángel); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Gomez-Roman, J. (Javier); Agorreta, J. (Jackeline); Subirada, F. (Francesc); Durany, O. (O.); Lopez-Picazo, J.M. (José M.); Blanco, D. (Daniel); Ezponda, T. (Teresa); Montuenga-Badia, L.M. (Luis M.); Aibar, E. (Elena); Maes, T. (Tamara); Rubio, A. (Ángel)Abstract Background Microarrays strategies, which allow for the characterization of thousands of alternative splice forms in a single test, can be applied to identify differential alternative splicing events. In this study, a novel splice array approach was developed, including the design of a high-density oligonucleotide array, a labeling procedure, and an algorithm to identify splice events. Results The array consisted of exon probes and thermodynamically balanced junction probes. Suboptimal probes were tagged and considered in the final analysis. An unbiased labeling protocol was developed using random primers. The algorithm used to distinguish changes in expression from changes in splicing was calibrated using internal non-spliced control sequences. The performance of this splice array was validated with artificial constructs for CDC6, VEGF, and PCBP4 isoforms. The platform was then applied to the analysis of differential splice forms in lung cancer samples compared to matched normal lung tissue. Overexpression of splice isoforms was identified for genes encoding CEACAM1, FHL-1, MLPH, and SUSD2. None of these splicing isoforms had been previously associated with lung cancer. Conclusions This methodology enables the detection of alternative splicing events in complex biological samples, providing a powerful tool to identify novel diagnostic and prognostic biomarkers for cancer and other pathologies.
- Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma.(Springer Nature, 2021) Carrasco-León, A. (Arantxa); Ezponda, T. (Teresa); Meydan, C. (Cem); Valcárcel-García, L.V. (Luis Vitores); Ordoñez, R. (Raquel); Kulis, M. (Marta); Garate, L. (Leire); Miranda, E. (Estibaliz); Segura, V. (Víctor); Guruceaga, E. (Elizabeth); Vilas-Zornoza, A. (Amaia); Alignani, D. (Diego); Pascual, M. (Marien); Amundarain, A. (Ane); Castro-Labrador, L. (Laura); San Martín, P. (Patxi); El-Omri, H. (Halima); Taha, R.Y. (Ruba Y.); Calasanz-Abinzano, M.J. (Maria Jose); Planes-Pedreño, F.J. (Francisco Javier); Paiva, B. (Bruno); Mason, C. E. (Christopher, E.); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier)Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
- Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution(2023) Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Diez-Campelo, M. (M.); Molero, A. (Antonieta); San-Martín-Uriz, P. (Patxi); Romero-Riojas, J.P. (Juan Pablo); Alfonso-Piérola, A. (Ana); San-Julian, M. (Mikel); Jimenez-Solas, T. (Tamara); Ezponda, T. (Teresa); Valcarcel, D. (David); Lopez, F. (Félix); Dupéré-Richer, D. (Daphné); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Montoro, J. (Julia); Mution, S. (Sandra); Hernaez, M. (Mikel); Serrano-Sanz, G. (Guillermo); Ainciburu-Fernández, M. (Marina); Prosper-Cardoso, F. (Felipe); Berastegui-Zufiaurre, N. (Nerea); Diaz-Mazquiaran, A. (Aintzane); Sanchez-Guijo, F.M. (Fermín M.)Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease. In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients
- Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma(2020) García-Torre, B. (Beatriz); Soler-Vila, P. (Paula); Taha, R.Y. (Ruba Y.); Beekman, R. (Renée); Rodriguez-Madoz, J.R. (Juan Roberto); El-Omri, H. (Halima); Charalampopoulou, S. (Stella); San-Jose-Eneriz, E. (Edurne); Martens, J.H.A. (Joost H. A.); Flicek, P. (Paul); Agirre, X. (Xabier); Stunnenberg, H.G. (Hendrik G.); Garate, L. (Leire); Kulis, M. (Marta); Mitsiades, C.S. (Constantine S.); Licht, J.D. (Jonathan D.); Carrasco-León, A. (Arantxa); Chapaprieta, V. (Vicente); Lara-Astiaso, D. (David); Ezponda, T. (Teresa); Ordóñez-Ciriza, R. (Raquel); Verdaguer-Dot, N. (Núria); Vilas-Zornoza, A. (Amaia); Campo, E. (Elías); Dupéré-Richer, D. (Daphné); Miranda, E. (Estibaliz); Duran-Ferrer, M. (Martí); Meydan, C. (Cem); Paiva, B. (Bruno); Vilarrasa-Blasi, R. (Roser); Gut, I. (Ivo); Melnick, A. (Ari); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Turrilas, R. (Rebeca); Clot, G. (Guillem); San-Miguel, J.F. (Jesús F.); Martin-Subero, J.I. (Jose Ignacio); Russiñol, N. (Nuria)Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
- The oncoprotein SF2/ASF promotes non-small cell lung cancer survival by enhancing survivin expression(American Association for Cancer Research, 2010-08-03) Torre, W. (Wenceslao); Pajares, M.J. (María José); Pio, R. (Rubén); Agorreta, J. (Jackeline); Lopez-Picazo, J.M. (José M.); Ezponda, T. (Teresa); Montuenga-Badia, L.M. (Luis M.); Echeveste, J.I. (José I.)Abstract Purpose: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non–small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis. Experimental Design: SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression. Results: Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis. Conclusion: This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression.