@article {736, title = {COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.}, journal = {Mol Syst Biol}, volume = {17}, year = {2021}, month = {2021 10}, pages = {e10387}, abstract = {

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

}, keywords = {Antiviral Agents, Computational Biology, Computer Graphics, COVID-19, Cytokines, Data Mining, Databases, Factual, Gene Expression Regulation, Host Microbial Interactions, Humans, Immunity, Cellular, Immunity, Humoral, Immunity, Innate, Lymphocytes, Metabolic Networks and Pathways, Myeloid Cells, Protein Interaction Mapping, SARS-CoV-2, Signal Transduction, Software, Transcription Factors, Viral Proteins}, issn = {1744-4292}, doi = {10.15252/msb.202110387}, author = {Ostaszewski, Marek and Niarakis, Anna and Mazein, Alexander and Kuperstein, Inna and Phair, Robert and Orta-Resendiz, Aurelio and Singh, Vidisha and Aghamiri, Sara Sadat and Acencio, Marcio Luis and Glaab, Enrico and Ruepp, Andreas and Fobo, Gisela and Montrone, Corinna and Brauner, Barbara and Frishman, Goar and Monraz G{\'o}mez, Luis Crist{\'o}bal and Somers, Julia and Hoch, Matti and Kumar Gupta, Shailendra and Scheel, Julia and Borlinghaus, Hanna and Czauderna, Tobias and Schreiber, Falk and Montagud, Arnau and Ponce de Leon, Miguel and Funahashi, Akira and Hiki, Yusuke and Hiroi, Noriko and Yamada, Takahiro G and Dr{\"a}ger, Andreas and Renz, Alina and Naveez, Muhammad and Bocskei, Zsolt and Messina, Francesco and B{\"o}rnigen, Daniela and Fergusson, Liam and Conti, Marta and Rameil, Marius and Nakonecnij, Vanessa and Vanhoefer, Jakob and Schmiester, Leonard and Wang, Muying and Ackerman, Emily E and Shoemaker, Jason E and Zucker, Jeremy and Oxford, Kristie and Teuton, Jeremy and Kocakaya, Ebru and Summak, G{\"o}k{\c c}e Ya{\u g}mur and Hanspers, Kristina and Kutmon, Martina and Coort, Susan and Eijssen, Lars and Ehrhart, Friederike and Rex, Devasahayam Arokia Balaya and Slenter, Denise and Martens, Marvin and Pham, Nhung and Haw, Robin and Jassal, Bijay and Matthews, Lisa and Orlic-Milacic, Marija and Senff Ribeiro, Andrea and Rothfels, Karen and Shamovsky, Veronica and Stephan, Ralf and Sevilla, Cristoffer and Varusai, Thawfeek and Ravel, Jean-Marie and Fraser, Rupsha and Ortseifen, Vera and Marchesi, Silvia and Gawron, Piotr and Smula, Ewa and Heirendt, Laurent and Satagopam, Venkata and Wu, Guanming and Riutta, Anders and Golebiewski, Martin and Owen, Stuart and Goble, Carole and Hu, Xiaoming and Overall, Rupert W and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Vega, Carlos and Grou{\`e}s, Valentin and Vazquez, Miguel and Porras, Pablo and Licata, Luana and Iannuccelli, Marta and Sacco, Francesca and Nesterova, Anastasia and Yuryev, Anton and de Waard, Anita and Turei, Denes and Luna, Augustin and Babur, Ozgun and Soliman, Sylvain and Valdeolivas, Alberto and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Helikar, Tom{\'a}{\v s} and Puniya, Bhanwar Lal and Modos, Dezso and Treveil, Agatha and Olbei, Marton and De Meulder, Bertrand and Ballereau, Stephane and Dugourd, Aur{\'e}lien and Naldi, Aur{\'e}lien and No{\"e}l, Vincent and Calzone, Laurence and Sander, Chris and Demir, Emek and Korcsmaros, Tamas and Freeman, Tom C and Aug{\'e}, Franck and Beckmann, Jacques S and Hasenauer, Jan and Wolkenhauer, Olaf and Wilighagen, Egon L and Pico, Alexander R and Evelo, Chris T and Gillespie, Marc E and Stein, Lincoln D and Hermjakob, Henning and D{\textquoteright}Eustachio, Peter and Saez-Rodriguez, Julio and Dopazo, Joaquin and Valencia, Alfonso and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {731, title = {De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {877-883}, abstract = {

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

}, keywords = {Child, Preschool, Cytoskeletal Proteins, Dwarfism, Exons, Gene Expression Regulation, Genetic Association Studies, Humans, Male, Neurodevelopmental Disorders, Protein Isoforms, RNA, Messenger, Sequence Deletion, Syndrome, Transcription Factors, Transcription Initiation Site, Transcription, Genetic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62017}, author = {Martinez-Delgado, Beatriz and Lopez-Martin, Estrella and Lara-Herguedas, Juli{\'a}n and Monzon, Sara and Cuesta, Isabel and Juli{\'a}, Miguel and Aquino, Virginia and Rodriguez-Martin, Carlos and Damian, Alejandra and Gonzalo, Irene and Gomez-Mariano, Gema and Baladron, Beatriz and Cazorla, Rosario and Iglesias, Gema and Roman, Enriqueta and Ros, Purificacion and Tutor, Pablo and Mellor, Susana and Jimenez, Carlos and Cabrejas, Maria Jose and Gonzalez-Vioque, Emiliano and Alonso, Javier and Bermejo-S{\'a}nchez, Eva and Posada, Manuel} } @article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {554, title = {Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.}, journal = {Br J Dermatol}, volume = {181}, year = {2019}, month = {2019 09}, pages = {512-522}, abstract = {

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in~situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What{\textquoteright}s already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

}, keywords = {Adolescent, Adult, Biopsy, Blister, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Extracellular Matrix, Extracellular Matrix Proteins, Female, Fibroblasts, Fibrosis, Gene Expression Regulation, Healthy Volunteers, Humans, Infant, Infant, Newborn, Male, Middle Aged, mutation, Periodontal Diseases, Photosensitivity Disorders, Primary Cell Culture, RNA-seq, Skin, Xeroderma Pigmentosum, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.17698}, author = {Chac{\'o}n-Solano, E and Le{\'o}n, C and D{\'\i}az, F and Garc{\'\i}a-Garc{\'\i}a, F and Garc{\'\i}a, M and Esc{\'a}mez, M J and Guerrero-Aspizua, S and Conti, C J and Menc{\'\i}a, {\'A} and Mart{\'\i}nez-Santamar{\'\i}a, L and Llames, S and P{\'e}vida, M and Carbonell-Caballero, J and Puig-Butill{\'e}, J A and Maseda, R and Puig, S and de Lucas, R and Baselga, E and Larcher, F and Dopazo, J and Del Rio, M} } @article {410, title = {LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Apr 16}, pages = {1488}, abstract = {

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

}, keywords = {Animals, Apoptosis, Cell Communication, Cell Survival, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Humans, Hypoglycemic Agents, Immunity, Innate, insulin, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Macrophages, Male, Mice, Mice, Inbred C57BL, Phenalenes, Receptors, Cytoplasmic and Nuclear, Streptozocin, T-Lymphocytes, Regulatory, Transplantation, Heterologous}, issn = {2041-1723}, doi = {10.1038/s41467-018-03943-0}, author = {Cobo-Vuilleumier, Nadia and Lorenzo, Petra I and Rodr{\'\i}guez, Noelia Garc{\'\i}a and Herrera G{\'o}mez, Irene de Gracia and Fuente-Martin, Esther and L{\'o}pez-Noriega, Livia and Mellado-Gil, Jos{\'e} Manuel and Romero-Zerbo, Silvana-Yanina and Baqui{\'e}, Mathurin and Lachaud, Christian Claude and Stifter, Katja and Perdomo, German and Bugliani, Marco and De Tata, Vincenzo and Bosco, Domenico and Parnaud, Geraldine and Pozo, David and Hmadcha, Abdelkrim and Florido, Javier P and Toscano, Miguel G and de Haan, Peter and Schoonjans, Kristina and S{\'a}nchez Palaz{\'o}n, Luis and Marchetti, Piero and Schirmbeck, Reinhold and Mart{\'\i}n-Montalvo, Alejandro and Meda, Paolo and Soria, Bernat and Berm{\'u}dez-Silva, Francisco-Javier and St-Onge, Luc and Gauthier, Benoit R} } @article {437, title = {Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 Oct 13}, pages = {35370}, abstract = {

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

}, keywords = {Aged, Animals, Co-Repressor Proteins, Codon, Nonsense, Cohort Studies, Comparative Genomic Hybridization, Consanguinity, DNA Mutational Analysis, Exome, Eye Proteins, Female, Gene Expression Regulation, Genes, Recessive, Homeodomain Proteins, Homozygote, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Retina, Retinal Dystrophies, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Spain, Trans-Activators, Transcription Factors}, issn = {2045-2322}, doi = {10.1038/srep35370}, author = {Corton, M and Avila-Fern{\'a}ndez, A and Campello, L and S{\'a}nchez, M and Benavides, B and L{\'o}pez-Molina, M I and Fern{\'a}ndez-S{\'a}nchez, L and S{\'a}nchez-Alcudia, R and da Silva, L R J and Reyes, N and Mart{\'\i}n-Garrido, E and Zurita, O and Fern{\'a}ndez-San Jos{\'e}, P and P{\'e}rez-Carro, R and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Garc{\'\i}a-Sandoval, B and Cuenca, N and Ayuso, C} } @article {529, title = {Differential expression in RNA-seq: a matter of depth.}, journal = {Genome Res}, volume = {21}, year = {2011}, month = {2011 Dec}, pages = {2213-23}, abstract = {

Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.

}, keywords = {Algorithms, Expressed Sequence Tags, Gene Expression Profiling, Gene Expression Regulation, Humans, Models, Genetic, Oligonucleotide Array Sequence Analysis}, issn = {1549-5469}, doi = {10.1101/gr.124321.111}, author = {Tarazona, Sonia and Garc{\'\i}a-Alcalde, Fernando and Dopazo, Joaquin and Ferrer, Alberto and Conesa, Ana} } @article {531, title = {Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.}, journal = {BMC Med Genomics}, volume = {4}, year = {2011}, month = {2011 Dec 30}, pages = {86}, abstract = {

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

}, keywords = {Animals, Cell Proliferation, Cell Survival, Cholesterol, Down-Regulation, Female, Gene Expression Regulation, Gene Knockout Techniques, Insulin Resistance, Insulin-Secreting Cells, Mice, obesity, Oxidation-Reduction, Phosphorylation, PPAR gamma, Signal Transduction, Transcription, Genetic, Transforming Growth Factor beta}, issn = {1755-8794}, doi = {10.1186/1755-8794-4-86}, author = {Vivas, Yurena and Martinez-Garcia, Cristina and Izquierdo, Adriana and Garcia-Garcia, Francisco and Callejas, Sergio and Velasco, Ismael and Campbell, Mark and Ros, Manuel and Dopazo, Ana and Dopazo, Joaquin and Vidal-Puig, Antonio and Medina-Gomez, Gema} } @article {552, title = {Functional genomics and networks: new approaches in the extraction of complex gene modules.}, journal = {Expert Rev Proteomics}, volume = {7}, year = {2010}, month = {2010 Feb}, pages = {55-63}, abstract = {

The engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.

}, keywords = {Gene Expression Regulation, Gene Regulatory Networks, Genomics, Protein Binding, Proteins, Systems biology}, issn = {1744-8387}, doi = {10.1586/epr.09.103}, author = {Minguez, Pablo and Dopazo, Joaquin} } @article {572, title = {Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.}, journal = {Stem Cells}, volume = {28}, year = {2010}, month = {2010 Mar 31}, pages = {407-18}, abstract = {

Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21\% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1\% or 5\% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5\% O(2), more than 50\% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50\%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.

}, keywords = {Angiopoietin-1, Animals, biomarkers, Cell Culture Techniques, Cell Differentiation, Cell Hypoxia, Cell Transplantation, Cells, Cultured, Down-Regulation, Embryonic Stem Cells, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Myocardial Infarction, Neovascularization, Physiologic, Oxygen, Pluripotent Stem Cells, Rats, Rats, Nude, Vascular Endothelial Growth Factor A}, issn = {1549-4918}, doi = {10.1002/stem.295}, author = {Prado-Lopez, Sonia and Conesa, Ana and Armi{\~n}{\'a}n, Ana and Mart{\'\i}nez-Losa, Magdalena and Escobedo-Lucea, Carmen and Gandia, Carolina and Tarazona, Sonia and Melguizo, Dario and Blesa, David and Montaner, David and Sanz-Gonz{\'a}lez, Silvia and Sep{\'u}lveda, Pilar and G{\"o}tz, Stefan and O{\textquoteright}Connor, Jos{\'e} Enrique and Moreno, Ruben and Dopazo, Joaquin and Burks, Deborah J and Stojkovic, Miodrag} }