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Now showing items 1 - 16 of 1755

  • DNA methylation dynamics in cellular commitment and differentiation

    Carrio, Elvira   Nunez-Alvarez, Yaiza   Peinado, Miguel A.  

    DNA methylation is an essential epigenetic modification for mammalian development and is crucial for the establishment and maintenance of cellular identity. Traditionally, DNA methylation has been considered as a permanent repressive epigenetic mark. However, the application of genome-wide approaches has allowed the analysis of DNA methylation in different genomic contexts, revealing a more dynamic regulation than originally thought, as active DNA methylation and demethylation occur during cell fate commitment and terminal differentiation. Recent data provide insights into the contribution of different epigenetic factors, and DNA methylation in particular, to the establishment of cellular memory during embryonic development and the modulation of cell type-specific gene regulation programs to ensure proper differentiation. This review summarizes published data regarding DNA methylation changes along lineage specification and differentiation programs. We also discuss the current knowledge about DNA methylation alterations occurring in physiological and pathological conditions such as aging and cancer.
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  • Truke,a web tool to check for and handle excel misidentified gene symbols

    Mallona, Izaskun   Peinado, Miguel A.  

    Background: Genomic datasets accompanying scientific publications show a surprisingly high rate of gene name corruption. This error is generated when files and tables are imported into Microsoft Excel and certain gene symbols are automatically converted into dates. Results: We have developed Truke, a fexible Web tool to detect, tag and fix, if possible, such misconversions. Aside, Truke is language and regional locale-aware, providing file format customization (decimal symbol, field sepator, etc.) following user's preferences. Conclusions: Truke is a data format conversion tool with a unique corrupted gene symbol detection utility. Truke is freely available without registration at http://maplab.cat/truke.
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  • Chainy:an universal tool for standardized relative quantification in real-time PCR

    Mallona, Izaskun   Diez-Villanueva, Anna   Martin, Berta   Peinado, Miguel A.  

    Chainy is a cross-platform web tool providing systematic pipelines and steady criteria to process real-time PCR data, including the calculation of efficiencies from raw data by kinetic methods, evaluation of the suitability of multiple references, standardized normalization using one or more references, and group-wise relative quantification statistical testing. We illustrate the utility of Chainy for differential expression and chromatin immunoprecipitation enrichment (ChIP-QPCR) analysis.
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  • Epigenetic deregulation of the COX pathway in cancer

    Cebola, Ines   Peinado, Miguel A.  

    Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients. (C) 2012 Elsevier Ltd. All rights reserved.
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  • Analysis of DNA Methylation by Amplification of Intermethylated Sites (AIMS)

    Jorda, Mireia   Rodriguez, Jairo   Frigola, Jord   Peinado, Miguel A.  

    DNA methylation is an epigenetic modification that plays a crucial role in the control of gene expression and chromosome structure in plants and mammalian cells. Multiple types of DNA fingerprinting techniques have been developed and applied to investigate DNA methylation profiles in different experimental settings, One of these techniques, the amplification of intermethylated sites (AIMS) is a simple approach appropriate for genome-wide estimates of DNA methylation and the discovery of specific methylated sequences. AIMS is based on the differential enzymatic digestion of genomic DNA with methylationsensitive and methylation-insensitive isoschizomers followed by restrained PCR amplification of methylated sequences. This method is appropriate to compare large series of samples and the simultaneous identification of hypo- and hypermethylation events. Applications of AIMS include the Study of DNA methylation changes in cancer and aging, and the discovery of DNA methylation in a social insect.
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  • METHOD OF DIAGNOSING CANCER AND REAGENTS THEREFOR

    The present invention provides methods for diagnosis and monitoring the efficacy of treatment of a cancer. More particularly, the methods of the invention comprise detecting an enhanced degree of chromatin modification within Chromosome 2 of the human genome from about map position 2ql4.1 to about map position 2ql4.3 in a sample derived from a subject. The methods include detecting an enhanced level of methylation, or detecting an enhanced level of modification of a histone positioned within the chromatin within the region of about 2ql4.1 to 2ql4.3 of Chromosome 2. The methods also include detecting a modulated level of expression of a gene within the region of about 2ql4.1 to 2ql4.3 of Chromosome 2. The gene may be selected from the group consisting of DEAD box polypeptide 18 (DDXl 8), translin (TSN), v-ral simian leukaemia viral oncogene homolog B (RALB), secretin recepto (SCTR), engrailed homolog 1 (ENl), macrophage receptor with collagenous structure (MARCO), protein tyrosine phosphatase non-receptor type 4 (PTPN4), insulin induced gene 2 (INSIG2), inhibin beta B (INHBB), GLI-Kruppel family member 2 (GLI2), FLJ10996, STEAP3, diazepam binding inhibitor (DBI), MGC10993, erythrocyte membrane protein band 4.1 like 5 (EPB41L5), FLJ14816, transcription factor CP2-like 1 (TFCP2L1).
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  • Functional CpG methylation system in a social insect RID A-6078-2008 RID A-5591-2008

    Wang, Ying   Jorda, Mireia   Jones, Peter L.   Maleszka, Ryszard   Ling, Xu   Robertson, Hugh M.   Mizzen, Craig A.   Peinado, Miguel A.   Robinson, Gene E.  

    DNA methylation systems are well characterized in vertebrates, but methylation in Drosophila melanogaster and other invertebrates remains controversial. Using the recently sequenced honey bee genome, we present a bioinformatic, molecular, and biochemical characterization of a functional DNA methylation system in an insect. We report on catalytically active orthologs of the vertebrate DNA methyltransferases Dnmt1 and Dnmt3a and b, two isoforms that contain a methyl-DNA binding domain, genomic 5-methyl-deoxycytosine, and CpG-methylated genes. The honey bee provides an opportunity to study the roles of methylation in social contexts.
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  • Chainy:an universal tool for standardized relative quantification in real-time PCR (vol 33,pg 1429,2017)

    Mallona, Izaskun   Diez-Villanueva, Anna   Martin, Berta   Peinado, Miguel A.  

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  • Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells RID A-5591-2008

    Rodriguez, Jairo   Vives, Laura   Jorda, Mireia   Morales, Cristina   Munoz, Mar   Vendrell, Elisenda   Peinado, Miguel A.  

    Methylation of the cytosine is the most frequent epigenetic modification of DNA in mammalian cells. In humans, most of the methylated cytosines are found in CpG-rich sequences within tandem and interspersed repeats that make up to 45 of the human genome, being Alu repeats the most common family. Demethylation of Alu elements occurs in aging and cancer processes and has been associated with gene reactivation and genomic instability. By targeting the unmethylated SmaI site within the Alu sequence as a surrogate marker, we have quantified and identified unmethylated Alu elements on the genomic scale. Normal colon epithelial cells contain in average 25486 +/- 10157 unmethylated Alus per haploid genome, while in tumor cells this figure is 41 995 +/- 17187 (P 0.004). There is an inverse relationship in Alu families with respect to their age and methylation status: the youngest elements exhibit the highest prevalence of the SmaI site (AluY: 42; AluS: 18, AluJ: 5) but the lower rates of unmethylation (AluY: 1.65%; AluS: 3.1%, AluJ: 12%). Data are consistent with a stronger silencing pressure on the youngest repetitive elements, which are closer to genes. Further insights into the functional implications of atypical unmethylation states in Alu elements will surely contribute to decipher genomic organization and gene regulation in complex organisms.
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  • Standardized approach for microsatellite instability detection in colorectal carcinomas

    Gonzalez-Garcia, Isabel   Moreno, Victor   Navarro, Matilde   Marti-Rague, Juan   Marcuello, Eugenio   Benasco, Carmen   Campos, Olga   Capella, Gabriel   Peinado, Miguel A.  

    Background: Ubiquitous mutations in microsatellite DNA sequences define a specific type of genetic instability, termed microsatellite instability (MSI). Various approaches have been used to identify the presence and degree of MSI. To define standard diagnostic criteria for MSI, we developed and tested a mathematical model. Methods: We designed an algorithm for the efficient characterization of MSI and used it to analyze data on six microsatellite markers in colorectal carcinoma and normal tissues from 415 patients. Theoretical models considering one, two, or three populations were tested against the data collected. Results: The observed frequencies of MSI in our series of samples best fit a two-population model, stable and unstable, defined by instability in two or more of four to six markers analyzed. MSI was observed in 7.5% of the tumors. The misclassification rate was less than 5% when any four loci were analyzed and less than 1% when the six markers were used. A stepwise strategy, consisting first of a bulk screening of two loci and then a second screening of two to four additional markers, provided excellent sensitivity (gtoreq97%) and specificity (100%). Tumors with MSI had distinctive genetic and clinicopathologic features, including better patient survival. Conclusion: To assess the presence of MSI in colorectal cancer, we have developed a simple, sensitive, and specific approach based on the apparent good fit of the data to a two-population model. Its application to a prospective series of patients with colorectal carcinomas demonstrates that the presence of MSI characterizes a subset of less aggressive tumors.
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  • Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

    Javierre, Biola M.   Fernandez, Agustin F.   Richter, Julia   Al-Shahrour, Fatima   Martin-Subero, J. Ignacio   Rodriguez-Ubreva, Javier   Berdasco, Maria   Fraga, Mario F.   O'Hanlon, Terrance P.   Rider, Lisa G.   Jacinto, Filipe V.   Javier Lopez-Longo, F.   Dopazo, Joaquin   Forn, Marta   Peinado, Miguel A.   Carreno, Luis   Sawalha, Amr H.   Harley, John B.   Siebert, Reiner   Esteller, Manel   Miller, Frederick W.  

    Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.
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  • GENETIC ANALYSIS OF BIOLOGICAL SAMPLES IN ARRAYED EXPANDED REPRESENTATIONS OF THEIR NUCLEIC ACIDS

    The invention provides a method for the genetic analysis of biological samples after generation and expansion of subsets representing their nucleic acids. Each subset contains a characteristic but arbitrarily selected representation. Different subsets display complementary representations. The method is specially suitable for the study of gene expression profiles. The subgrouping is done by RNA arbitrarily primed PCR (RAP-PCR).
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  • regioneR:an R/Bioconductor package for the association analysis of genomic regions based on permutation tests

    Gel, Bernat   Diez-Villanueva, Anna   Serra, Eduard   Buschbeck, Marcus   Peinado, Miguel A.   Malinverni, Roberto  

    Motivation: Statistically assessing the relation between a set of genomic regions and other genomic features is a common challenging task in genomic and epigenomic analyses. Randomization based approaches implicitly take into account the complexity of the genome without the need of assuming an underlying statistical model. Summary: regioneR is an R package that implements a permutation test framework specifically designed to work with genomic regions. In addition to the predefined randomization and evaluation strategies, regioneR is fully customizable allowing the use of custom strategies to adapt it to specific questions. Finally, it also implements a novel function to evaluate the local specificity of the detected association.
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  • The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

    Jorda, Mireia   Diez-Villanueva, Anna   Mallona, Izaskun   Martin, Berta   Lois, Sergi   Barrera, Victor   Esteller, Manel   Vavouri, Tanya   Peinado, Miguel A.  

    Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high / low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.
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  • Regional Distribution of Immunoreactive Somatostatin in the Bovine Pineal Gland

    Peinado, Miguel A.   Viader, Mercedes   Puig-Domingo, Manuel   Hernández, Guadalberto   Reiter, Russel J.   Webb, Susan M.  

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  • Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE(2) in colorectal cancer

    Cebola, Ines   Custodio, Joaquin   Munoz, Mar   Diez-Villanueva, Anna   Pare, Laia   Prieto, Patricia   Ausso, Susanna   Coll-Mulet, Llorenc   Bosca, Lisardo   Moreno, Victor   Peinado, Miguel A.  

    Background: Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells. Results: Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E-2 (PGE(2)) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors. Conclusions: The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.
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