Instituto Gulbenkian Of Ciencia Igc

Oeiras, Portugal

Instituto Gulbenkian Of Ciencia Igc

Oeiras, Portugal
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PubMed | University of Porto, Abel Salazar Biomedical Sciences Institute, Andalusian Center for Developmental Biology, Instituto Gulbenkian Of Ciencia Igc and University of Seville
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and PS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin 2 (LM-2), 1 and 4 integrin, when compared with Ecad-competent ones. We showed that LM-2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-2. This is the rst evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-2 signalling regulators as molecular targets to impair gastric cancer progression.


PubMed | San Francesco Hospital ASL, Polytechnic Institute of Porto, University Pompeu Fabra, University of Abderrahmane Mira de Béjaïa and 5 more.
Type: Journal Article | Journal: Genome biology and evolution | Year: 2015

A polymorphic inversion that lies on chromosome 17q21 comprises two major haplotype families (H1 and H2) that not only differ in orientation but also in copy-number. Although the processes driving the spread of the inversion-associated lineage (H2) in humans remain unclear, a selective advantage has been proposed for one of its subtypes. Here, we genotyped a large panel of individuals from previously overlooked populations using a custom array with a unique panel of H2-specific single nucleotide polymorphisms and found a patchy distribution of H2 haplotypes in Africa, with North Africans displaying a higher frequency of inverted subtypes, when compared with Sub-Saharan groups. Interestingly, North African H2s were found to be closer to non-African chromosomes further supporting that these populations may have diverged more recently from groups outside Africa. Our results uncovered higher diversity within the H2 family than previously described, weakening the hypothesis of a strong selective sweep on all inverted chromosomes and suggesting a rather complex evolutionary history at this locus.


Alves J.M.,University of Porto | Alves J.M.,Instituto Gulbenkian Of Ciencia Igc | Chikhi L.,Instituto Gulbenkian Of Ciencia Igc | Chikhi L.,French National Center for Scientific Research | And 2 more authors.
Genome Biology and Evolution | Year: 2014

For decades, chromosomal inversions have been regarded as fascinating evolutionary elements as they are expected to suppress recombination between chromosomes with opposite orientations, leading to the accumulation of genetic differences between the twoconfigurations over time.Here,makinguseofpublicly availablepopulationgenotypedata for the largestpolymorphic inversion in thehumangenome(8p23-inv),weassessedwhether this inhibitory effect of inversion rearrangements ledtosignificantdifferences in the recombination landscape of two homologous DNA segments, with opposite orientation. Our analysis revealed that the accumulation of genetic differentiation is positively correlated with the variation in recombination profiles. The observed recombination dissimilarity between inversion types is consistent across all populations analyzed and surpasses the effects of geographic structure, suggesting that both structures (orientations) have been evolving independently over an extended period of time, despite being subjected tothe very samedemographichistory.Aside this mainly independent evolution,wealso identified a short segment (350 kb, <10% of the whole inversion) in the central region of the inversion where the genetic divergence between the two structural haplotypes is diminished. Although it is difficult to demonstrate it, this could be due to gene flow (possibly via double-crossing over events), which is consistent with the higher recombination rates surrounding this segment. This study demonstrates for the first time that chromosomal inversions influence the recombination landscape at afine-scale andhighlights the role of these rearrangements as drivers of genome evolution. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.


Alves J.M.,University of Porto | Alves J.M.,Instituto Gulbenkian Of Ciencia Igc | Lopes A.M.,University of Porto | Chikhi L.,Instituto Gulbenkian Of Ciencia Igc | And 2 more authors.
Current Genomics | Year: 2012

With the aid of novel and powerful molecular biology techniques, recent years have witnessed a dramatic increase in the number of studies reporting the involvement of complex structural variants in several genomic disorders. In fact, with the discovery of Copy Number Variants (CNVs) and other forms of unbalanced structural variation, much attention has been directed to the detection and characterization of such rearrangements, as well as the identification of the mechanisms involved in their formation. However, it has long been appreciated that chromosomes can undergo other forms of structural changes - balanced rearrangements - that do not involve quantitative variation of genetic material. Indeed, a particular subtype of balanced rearrangement - inversions - was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome. © 2012 Bentham Science Publishers.


Grau D.J.,Massachusetts General Hospital | Grau D.J.,Harvard University | Antao J.M.,Massachusetts General Hospital | Antao J.M.,Harvard University | And 3 more authors.
Cold Spring Harbor Symposia on Quantitative Biology | Year: 2010

Silencing of homeotic genes requires the Polycomb repressive complex 1 (PRC1) family of protein complexes, which are composed of Polycomb-group (PcG) proteins and frequently include other subunits. We discuss here two aspects of PRC1 that might contribute to this activity. Inhibiting the action of remodeling factors via chromatin compaction is believed to be one mechanism by which PRC1 represses genes. We show that PRC1s from fly and mouse have conserved this activity as complexes. Additionally, we provide evidence that a different subunit in the mouse complex retains the conserved repression activity and that activity appears to be mediated by charge interactions. We show that Zeste interacts specifically with the Ph subunit of PRC1 and discuss the possibility of these factors contributing to spreading of PRC1 complexes. Our results suggest that one aspect of PRC1 repression is likely to be mediated by charge-charge interactions. © 2010 Cold Spring Harbor Laboratory Press.


Sanchez L.,CSIC - Biological Research Center | Chaouiya C.,Instituto Gulbenkian Of Ciencia Igc
BMC Systems Biology | Year: 2016

Background: Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules. Results: Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and ß-catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub-networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand. Conclusions: Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet. © 2016 Sánchez and Chaouiya.


Nogly P.,New University of Lisbon | Matias P.M.,New University of Lisbon | De Rosa M.,Instituto Gulbenkian Of Ciencia Igc | Castro R.,New University of Lisbon | And 3 more authors.
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

The first structure of a bacterial -phosphoglucomutase with an overall fold similar to eukaryotic phosphomannomutases is reported. Unlike most -phosphoglucomutases within the -d-phosphohexomutase superfamily, it belongs to subclass IIb of the haloacid dehalogenase superfamily (HADSF). It catalyzes the reversible conversion of -glucose 1-phosphate to glucose 6-phosphate. The crystal structure of -phosphoglucomutase from Lactococcus lactis (APGM) was determined at 1.514;Å resolution and contains a sulfate and a glycerol bound at the enzyme active site that partially mimic the substrate. A dimeric form of APGM is present in the crystal and in solution, an arrangement that may be functionally relevant. The catalytic mechanism of APGM and its strict specificity towards -glucose 1-phosphate are discussed. © 2013 International Union of Crystallography Printed in Singapore - all rights reserved. © 2013.


PubMed | Instituto Gulbenkian Of Ciencia Igc and New University of Lisbon
Type: | Journal: BioMed research international | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most prevalent cause of liver disease worldwide and afflicts adults and children as currently associated with obesity and insulin resistance. Even though lately some advances have been made to elucidate the mechanism and causes of the disease much remains unknown about NAFLD. The aim of this paper is to discuss the present knowledge regarding the pathogenesis of the disease aiming at the initial steps of NAFLD development, when inflammation impinges on fat liver deposition. At this stage, the Kupffer cells attain a prominent role. This knowledge becomes subsequently relevant for the development of future diagnostic, prevention, and therapeutic options for the management of NAFLD.


PubMed | University of Porto, Centro Hospitalar Of S Joao, Instituto Gulbenkian Of Ciencia Igc and Centro Hospitalar Of Coimbra
Type: | Journal: Scientific reports | Year: 2016

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP- and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.


PubMed | CSIC - Biological Research Center and Instituto Gulbenkian Of Ciencia Igc
Type: Journal Article | Journal: BMC systems biology | Year: 2016

Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules.Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and -catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub-networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand.Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet.

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