Papers by Valeriano López-Segura
Translational Medicine Communications, 2018
Background: Autoimmune diseases are syndromes characterized by an immune response against self-an... more Background: Autoimmune diseases are syndromes characterized by an immune response against self-antigens. They are complex pathologies associated with a variety of genetic determinants, but these genes cannot fully explain the aetiology of autoimmune disorders. Ikaros is a transcription factor that plays a major role in lymphoid differentiation. Methods: In this study, we characterized the expression profiles of Ikaros isoforms by quantifying the interexonic regions of patients diagnosed with Sjögren's syndrome, systemic lupus erythaematosus, systemic sclerosis and rheumatoid arthritis in RNA extracted from peripheral blood. REST software was used for relative quantification and Hierarchical clustering analysis was performed using Cluster and TreeView.
Endocrine Connections, 2017
Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic m... more Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro-and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues.
La epigenética ha tomado una importancia primordial en los últimos años en lo que a regulación gé... more La epigenética ha tomado una importancia primordial en los últimos años en lo que a regulación génica se refiere. Lo que hace unos años se creía respecto al funcionamiento de los factores de transcripción ha quedado totalmente obsoleto y hoy nadie duda de la necesidad de una regulación epigenética sobre la función de los factores de transcripción. Sin embargo, más allá de la función puntual sobre genes concretos, es la estabilidad generacional lo que hace de la epigenética un mecanismo primordial para dar entidad a las células. Es decir, la capacidad de ser heredados generación tras generación es lo que determina el verdadero valor de los mecanismos epigenéticos y es en esta memoria epigenética en lo que se basa una célula para saber que es y que función tiene dentro del organismo. Desde este punto de vista, el cáncer es en gran medida una enfermedad de la memoria celular, un desconocimiento de si misma que hace a la célula tumoral comportarse como lo que no es. De este modo, uno de los mecanismos epigenéticos más importantes en la generación de un tumor es el proceso de hipometilación que provoca la activación de genes erróneamente, entre los que, en muchas ocasiones, se encuentran oncogenes, ya lo sea por mutaciones o por la propia desrregulación en su expresión.
The Ikaros gene family is a group of transcriptional factors (Ikaros, Helios, Aiolos, Eos y Pegas... more The Ikaros gene family is a group of transcriptional factors (Ikaros, Helios, Aiolos, Eos y Pegasus) which play an important role in lymphoid development. Besides acting as a classic transcriptional factor, this proteins also are involved in chromatin remodelling complexes.
This gene family encodes zinc finger DNA-binding proteins. All the members of Ikaros family produce multiple isoforms via alternative mRNA splicing. Some of them are dominant-negative isoforms with a non functional DNA-binding domain. Those isoforms have been found in patients with acute lymphoblastic leukemia and may have a role in the development of leukemias or lymphomas. However, some of this dominant-negative isoforms are also found in healthy people.
Our group have characterized new Helios isoforms in haematopoietic and non haematopoietic cellular lines. Several of this new isoforms have novel alternatives exons located in differents introns (He.1+2a,He.1+3a,He.1+5a), Moreover we have cloned isoforms that present a criptic process site in the exón 3 (He.1v y He.6v) and a new dominat-negative isoforma named He.S, which is generated by a novel splicing mechanism.
We have studied the intracellular localization and the protein-protein interaction of some of these isoforms. Moreover, we have analized the Histones acetilation status. Our results suggest that He.1v plays an important role in the histones acetilation, specifically in the Histone H3 and confirms that this proteins are involved in remodelling complexes. The comparative study of differents isoforms will allow us to know more about the role of this family in normal lymphoid development and its possible implication in tumor development.
The oxidative damage generated by Lead (Pb) through Fenton- like reactions has been indicated by ... more The oxidative damage generated by Lead (Pb) through Fenton- like reactions has been indicated by years as a source of genotoxic damage, it transforms nucleotide structures to its oxidized forms like 8-oxoguanine and other molecules that in- directly may produce 5-hydroxymethylcytocine (5hmC). This DNA damage is recognized by the base excision repair system (BER) in standard conditions. When high Pb exposure occurs, this system has been described as non functional by the inhi- bition of Apurinic Endonuclease 1 (APE1).When the oxidized nucleotides are recognized by the non functional BER system it generates an apurinic site that could be detected by the Comet assay. On the other hand, the effect of the oxidative stress could produce a loss of melthylation marks trough synthesis of 5hmC. The aim of this study was to correlate the blood Pb levels with the DNA damage in a population occupationally exposed, and additionally to scan the behavior of the global epigenetic markers 5-methylcytocine (5mC) and 5hmC. To achieve this, a population of 60 participants were selected and classi ed in two equally sized groups by age and gender. Lifestyle habits and symptoms were included among the variables to be ana- lyzed. Blood samples were taken to measure DNA damage by the alkaline Comet assay. Blood Pb concentration, 5mC and 5hmC was quanti ed by Anodic Stripping Voltammetry and ELISA Assay respectively. We found differences between the exposed and non exposed groups regarding DNA damage, but it indicates a negative relation among damage and Pb levels. Moreover, dose-dependent correlation were not found between Pb levels and DNA damage. Finally, the epigenetic markers 5hmC and 5mC seems not to change among the exposed and non-exposed individuals but interestingly, it shows signi cant differences when controlling by alcohol intake and drinking rate.
Pensamos en las ranas como animales de sangre fría, que viven en su mayoría cerca de ríos, quebra... more Pensamos en las ranas como animales de sangre fría, que viven en su mayoría cerca de ríos, quebradas, lagos, estanques y charcos. Sin embargo, estos extraordinarios organismos son una muestra exitosa de adaptación a distintos tipos de hábitats. A lo largo de su evolución, las ranas han logrado ingeniárselas para manejar la deseca- ción en áreas desérticas, conquistar el suelo y las copas de los árboles, y hasta son capaces de tolerar condicio- nes de congelamiento extremo.
A variety of genetic alterations are considered hallmarks of cancer development and progression. ... more A variety of genetic alterations are considered hallmarks of cancer development and progression. The Ikaros gene family, encoding for key transcription factors in hematopoietic development, provides several examples as genetic defects in these genes are associated with the development of different types of leukemia. However, the complex patterns of expression of isoforms in Ikaros family genes has prevented their use as clinical markers.
In this study, we propose the use of the expression profiles of the Ikaros isoforms to classify various hematological tumor diseases. We have standardized a quantitative PCR protocol to estimate the expression levels of the Ikaros gene exons. Our analysis reveals that these levels are associated with specific types of leukemia and we have found differences in the levels of expression relative to five interexonic Ikaros regions for all diseases studied. In conclusion, our method has allowed us to precisely discriminate between B-ALL, CLL and MM cases. Differences between the groups of lymphoid and myeloid pathologies were also identified in the same way.
Revista Colombiana de Cancerología, 2013
Introducción: La investigación en cáncer debe generar conocimiento que contribuya al control de l... more Introducción: La investigación en cáncer debe generar conocimiento que contribuya al control de la enfermedad en sus diversos aspectos; en este sentido, conocer los temas que más se investigan, los recursos y las capacidades con que cuenta el país, permitirán hacer ajustes enfocados a lograr un mayor impacto en el control del cáncer. Objetivo: Describir y caracterizar las capacidades en ciencia y tecnología, producción bibliográ ca y proyectos de investigación en cáncer, que tuvo Colombia entre 2000 y 2010. Materiales y métodos: Se realizaron consultas a las plataformas ScienTI y SIGP de Colciencias, para identi car investigadores, grupos de investigación, instituciones y proyectos. Para determinar la producción bibliográ ca asociada, se consultaron las bases de datos Web of Science, Scopus y PubMed. Resultados: Se identificaron 1.982 investigadores asociados a 546 grupos, 129 instituciones avaladoras y 2.481 productos de investigación en cáncer; los tipos de cáncer más estudiados correspondieron a cuello del útero, estómago, mama, leucemias e hígado. Las líneas de investigación más desarrolladas fueron diagnóstico y tratamiento, y biología del cáncer. Los tipos de publicación más frecuentes fueron pruebas diagnósticas, series de casos y los artículos de opinión. El promedio del factor de impacto de las revistas donde se hicieron publicaciones fue de 2,53. Conclusiones: A pesar del incremento observado en las capacidades nacionales para la investigación del cáncer, se identi caron limitaciones en la visibilidad de los productos generados y escasa investigación en algunos cánceres de alta incidencia en el territorio colombiano.
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Papers by Valeriano López-Segura
This gene family encodes zinc finger DNA-binding proteins. All the members of Ikaros family produce multiple isoforms via alternative mRNA splicing. Some of them are dominant-negative isoforms with a non functional DNA-binding domain. Those isoforms have been found in patients with acute lymphoblastic leukemia and may have a role in the development of leukemias or lymphomas. However, some of this dominant-negative isoforms are also found in healthy people.
Our group have characterized new Helios isoforms in haematopoietic and non haematopoietic cellular lines. Several of this new isoforms have novel alternatives exons located in differents introns (He.1+2a,He.1+3a,He.1+5a), Moreover we have cloned isoforms that present a criptic process site in the exón 3 (He.1v y He.6v) and a new dominat-negative isoforma named He.S, which is generated by a novel splicing mechanism.
We have studied the intracellular localization and the protein-protein interaction of some of these isoforms. Moreover, we have analized the Histones acetilation status. Our results suggest that He.1v plays an important role in the histones acetilation, specifically in the Histone H3 and confirms that this proteins are involved in remodelling complexes. The comparative study of differents isoforms will allow us to know more about the role of this family in normal lymphoid development and its possible implication in tumor development.
In this study, we propose the use of the expression profiles of the Ikaros isoforms to classify various hematological tumor diseases. We have standardized a quantitative PCR protocol to estimate the expression levels of the Ikaros gene exons. Our analysis reveals that these levels are associated with specific types of leukemia and we have found differences in the levels of expression relative to five interexonic Ikaros regions for all diseases studied. In conclusion, our method has allowed us to precisely discriminate between B-ALL, CLL and MM cases. Differences between the groups of lymphoid and myeloid pathologies were also identified in the same way.
This gene family encodes zinc finger DNA-binding proteins. All the members of Ikaros family produce multiple isoforms via alternative mRNA splicing. Some of them are dominant-negative isoforms with a non functional DNA-binding domain. Those isoforms have been found in patients with acute lymphoblastic leukemia and may have a role in the development of leukemias or lymphomas. However, some of this dominant-negative isoforms are also found in healthy people.
Our group have characterized new Helios isoforms in haematopoietic and non haematopoietic cellular lines. Several of this new isoforms have novel alternatives exons located in differents introns (He.1+2a,He.1+3a,He.1+5a), Moreover we have cloned isoforms that present a criptic process site in the exón 3 (He.1v y He.6v) and a new dominat-negative isoforma named He.S, which is generated by a novel splicing mechanism.
We have studied the intracellular localization and the protein-protein interaction of some of these isoforms. Moreover, we have analized the Histones acetilation status. Our results suggest that He.1v plays an important role in the histones acetilation, specifically in the Histone H3 and confirms that this proteins are involved in remodelling complexes. The comparative study of differents isoforms will allow us to know more about the role of this family in normal lymphoid development and its possible implication in tumor development.
In this study, we propose the use of the expression profiles of the Ikaros isoforms to classify various hematological tumor diseases. We have standardized a quantitative PCR protocol to estimate the expression levels of the Ikaros gene exons. Our analysis reveals that these levels are associated with specific types of leukemia and we have found differences in the levels of expression relative to five interexonic Ikaros regions for all diseases studied. In conclusion, our method has allowed us to precisely discriminate between B-ALL, CLL and MM cases. Differences between the groups of lymphoid and myeloid pathologies were also identified in the same way.