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Villasante A.,Tumour Suppression Group | Piazzolla D.,Tumour Suppression Group | Li H.,Tumour Suppression Group | Gomez-Lopez G.,Bioinformatics Unit | And 2 more authors.
Cell Cycle | Year: 2011

Nanog levels in pluripotent stem cells are heterogeneous and reflect two different and interchangeable cell states, respectively poised to self-renew (Nanog-high subpopulation) or to differentiate (Nanog-low subpopulation). However, little is known about the mechanisms responsible for this pattern of Nanog expression. Here, we have examined the impact of the histone methyltransferase Ezh2 on pluripotent stem cells and on Nanog expression. Interestingly, induced pluripotent stem (iPS) cells lacking Ezh2 presented higher levels of Nanog due to a relative expansion of the Nanog-high subpopulation, and this was associated to severe defects in differentiation. Moreover, we found that the Nanog promoter in embryonic stem (ES) cells and iPS cells coexists in two univalent chromatin configurations, one characterized by H3K4me3 and the other by H3K27me3, being the latter dependent on the presence of functional Ezh2. Finally, the levels of expression of Ezh2, as well as the amount of H3K27me3 present at the Nanog promoter, were higher in the Nanog-low subpopulation of ES/iPS cells. together, these data indicate that Ezh2 directly regulates the epigenetic status of the Nanog promoter affecting the balance of Nanog expression in pluripotent stem cells and, therefore, the equilibrium between self-renewal and differentiation. © 2011 Landes Bioscience. Source


Martino D.,Murdoch Childrens Research Institute | Loke Y.J.,Early Life Epigenetics Group | Loke Y.J.,University of Melbourne | Gordon L.,Bioinformatics Unit | And 7 more authors.
Genome Biology | Year: 2013

Background: The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy. Results: In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change. Conclusions: Our findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program. © 2013 Martino et al.; licensee BioMed Central Ltd. Source


Abia D.,Bioinformatics Unit
Immunology Letters | Year: 2014

Although the T cell antigen receptor (TCR) is long known to contain multiple signaling subunits (CD3γ, CD3δ, CD3e{open} and CD3ζ), their role in signal transduction is still not well understood. The presence of at least one immunoreceptor tyrosine-based activation motif (ITAM) in each CD3 subunit has led to the idea that the multiplication of such elements essentially serves to amplify signals. However, the evolutionary conservation of non-ITAM sequences suggests that each CD3 subunit is likely to have specific non-redundant roles at some stage of development or in mature T cell function. The CD3e{open} subunit is paradigmatic because in a relatively short cytoplasmic sequence (~55 amino acids) it contains several docking sites for proteins involved in intracellular trafficking and signaling, proteins whose relevance in T cell activation is slowly starting to be revealed. In this review we will summarize our current knowledge on the signaling effectors that bind directly to the TCR and we will propose a hierarchy in their response to TCR triggering. © 2014 Elsevier B.V. Source


Carro A.,Bioinformatics Unit | Rico D.,Structural Computational Biology Group | Rueda O.M.,Cancer Research UK | Diaz-Uriarte R.,Structural Computational Biology Group | Pisano D.G.,Bioinformatics Unit
Nucleic Acids Research | Year: 2010

waviCGH is a versatile web server for the analysis and comparison of genomic copy number alterations in multiple samples from any species. waviCGH processes data generated by high density SNP-arrays, array-CGH or copy-number calls generated by any technique. waviCGH includes methods for pre-processing of the data, segmentation, calling of gains and losses, and minimal common regions determination over a set of experiments. The server is a user-friendly interface to the analytical methods, with emphasis on results visualization in a genomic context. Analysis tools are introduced to the user as the different steps to follow in an experimental protocol. All the analysis steps generate high quality images and tables ready to be imported into spreadsheet programs. Additionally, for human, mouse and rat, altered regions are represented in a biological context by mapping them into chromosomes in an integrated cytogenetic browser. waviCGH is available at http://wavi.bioinfo.cnio.es. © The Author(s) 2010. Published by Oxford University Press. Source


Munoz-Espin D.,Tumor Suppression Group | Canamero M.,Histopathology Unit | Maraver A.,Tumor Suppression Group | Gomez-Lopez G.,Bioinformatics Unit | And 12 more authors.
Cell | Year: 2013

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence. © 2013 Elsevier Inc. Source

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