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Fuentes D.,University of Santiago de Chile | Meneses M.,University of Santiago de Chile | Nunes-Nesi A.,Max Planck Institutfur Molekulare Pflanzenphysiologie | Nunes-Nesi A.,Federal University of Viçosa | And 9 more authors.
Plant Physiology | Year: 2011

Mitochondrial complex II (succinate dehydrogenase [SDH]) plays roles both in the tricarboxylic acid cycle and the respiratory electron transport chain. In Arabidopsis (Arabidopsis thaliana), its flavoprotein subunit is encoded by two nuclear genes, SDH1-1 and SDH1-2. Here, we characterize heterozygous SDH1-1/sdh1-1 mutant plants displaying a 30% reduction in SDH activity as well as partially silenced plants obtained by RNA interference. We found that these plants displayed significantly higher CO 2 assimilation rates and enhanced growth than wild-type plants. There was a strong correlation between CO 2 assimilation and stomatal conductance, and both mutant and silenced plants displayed increased stomatal aperture and density. By contrast, no significant differences were found for dark respiration, chloroplastic electron transport rate, CO 2 uptake at saturating concentrations of CO 2, or biochemical parameters such as the maximum rates of carboxylation by Rubisco and of photosynthetic electron transport. Thus, photosynthesis is enhanced in SDH-deficient plants by a mechanism involving a specific effect on stomatal function that results in improved CO 2 uptake. Metabolic and transcript profiling revealed that mild deficiency in SDH results in limited effects on metabolism and gene expression, and data suggest that decreases observed in the levels of some amino acids were due to a higher flux to proteins and other nitrogen-containing compounds to support increased growth. Strikingly, SDH1-1/ sdh1-1 seedlings grew considerably better in nitrogen-limiting conditions. Thus, a subtle metabolic alteration may lead to changes in important functions such as stomatal function and nitrogen assimilation. © 2011 American Society of Plant Biologists. All Rights Reserved.


Meneses C.,Andrés Bello University | Orellana A.,Andrés Bello University | Orellana A.,Center for Genome Regulation
Biological Research | Year: 2013

New fruit varieties are needed to satisfy consumers, and the industry is facing new challenges in order to respond to these demands. The emergence of genomic tools is releasing information on polymorphisms that can be utilized to expedite breeding processes in species that are difficult to breed, given the long periods of time required to get new varieties. The present review describes the current stages of the ongoing efforts that are being taken to apply these technologies to obtain varieties with improved fruit quality in species of the family Rosaceae.


Puelma T.,Center for Genome Regulation | Puelma T.,University of Computer Science of Chile | Gutierrez R.A.,Center for Genome Regulation | Soto A.,University of Computer Science of Chile
Bioinformatics | Year: 2012

Motivation: Massive amounts of genome-wide gene expression data have become available, motivating the development of computational approaches that leverage this information to predict gene function. Among successful approaches, supervised machine learning methods, such as Support Vector Machines (SVMs), have shown superior prediction accuracy. However, these methods lack the simple biological intuition provided by co-expression networks (CNs), limiting their practical usefulness.Results: In this work, we present Discriminative Local Subspaces (DLS), a novel method that combines supervised machine learning and co-expression techniques with the goal of systematically predict genes involved in specific biological processes of interest. Unlike traditional CNs, DLS uses the knowledge available in Gene Ontology (GO) to generate informative training sets that guide the discovery of expression signatures: expression patterns that are discriminative for genes involved in the biological process of interest. By linking genes co-expressed with these signatures, DLS is able to construct a discriminative CN that links both, known and previously uncharacterized genes, for the selected biological process. This article focuses on the algorithm behind DLS and shows its predictive power using an Arabidopsis thaliana dataset and a representative set of 101 GO terms from the Biological Process Ontology. Our results show that DLS has a superior average accuracy than both SVMs and CNs. Thus, DLS is able to provide the prediction accuracy of supervised learning methods while maintaining the intuitive understanding of CNs. © The Author 2012. Published by Oxford University Press.


Kraiser T.,Center for Genome Regulation | Gras D.E.,Center for Genome Regulation | Gutierrez A.G.,Helmholtz Center for Environmental Research | Gonzalez B.,University of Santiago de Chile | Gutierrez R.A.,Center for Genome Regulation
Journal of Experimental Botany | Year: 2011

Nitrogen (N) is the mineral nutrient required in the greatest amount and its availability is a major factor limiting growth and development of plants. As sessile organisms, plants have evolved different strategies to adapt to changes in the availability and distribution of N in soils. These strategies include mechanisms that act at different levels of biological organization from the molecular to the ecosystem level. At the molecular level, plants can adjust their capacity to acquire different forms of N in a range of concentrations by modulating the expression and function of genes in different N uptake systems. Modulation of plant growth and development, most notably changes in the root system architecture, can also greatly impact plant N acquisition in the soil. At the organism and ecosystem levels, plants establish associations with diverse microorganisms to ensure adequate nutrition and N supply. These different adaptive mechanisms have been traditionally discussed separately in the literature. To understand plant N nutrition in the environment, an integrated view of all pathways contributing to plant N acquisition is required. Towards this goal, in this review the different mechanisms that plants utilize to maintain an adequate N supply are summarized and integrated. © 2011 The Author.


Klein A.D.,Weizmann Institute of Science | Alvarez A.,University of Santiago de Chile | Zanlungo S.,University of Santiago de Chile | Zanlungo S.,Center for Genome Regulation
Pediatric Endocrinology Reviews | Year: 2014

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal cholesterol storage disorder that arises from loss-of-function mutations in either the NPC1 or NPC2 genes. Both genes code for proteins involved in lysosomal cholesterol efflux. NPC is often diagnosed in early childhood, with patients typically displaying cerebellar ataxia, difficulties in speaking and swallowing, and progressive dementia. Unfortunately, to date, there is no curative treatment for this devastating and fatal disorder, although several symptomatic manifestations of NPC are treatable. In this review, we discuss the cell biology of the disease, clinical aspects, diagnostic approaches, and current and potential therapeutic strategies against NPC.


Vazquez M.C.,University of Santiago de Chile | Balboa E.,University of Santiago de Chile | Alvarez A.R.,University of Santiago de Chile | Zanlungo S.,University of Santiago de Chile | Zanlungo S.,Center for Genome Regulation
Oxidative Medicine and Cellular Longevity | Year: 2012

Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease. Copyright © 2012 Mary Carmen Vzquez et al.


Arguello G.,University of Santiago de Chile | Arguello G.,Center for Genome Regulation | Balboa E.,University of Santiago de Chile | Arrese M.,University of Santiago de Chile | And 2 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. NAFLD hallmark is the excessive hepatic accumulation of neutral lipids that result from an imbalance between lipid availability and lipid removal. Recent data suggest that disturbed hepatic cholesterol homeostasis and liver free cholesterol (FC) accumulation are relevant to the pathogenesis of NAFLD/NASH. Hepatic FC accumulation in NAFLD results from alterations in intracellular cholesterol transport and from unbalanced cellular cholesterol homeostasis characterized by activation of cholesterol biosynthetic pathways, increased cholesterol de-esterification and attenuation of cholesterol export and bile acid synthesis pathways. FC accumulation leads to liver injury through the activation of intracellular signaling pathways in Kupffer cells (KCs), Stellate cells (HSCs) and hepatocytes. The activation of KCs and HSCs promotes inflammation and fibrogenesis. In addition, FC accumulation in liver mitochondria induces mitochondrial dysfunction, which results in increasing production of reactive oxygen species, and triggers the unfolded protein response in the endoplasmic reticulum (ER) causing ER stress and apoptosis. These events create a vicious circle that contributes to the maintenance of steatosis and promotes ongoing hepatocyte death and liver damage, which in turn may translate into disease progression. In the present review we summarize the current knowledge on dysregulated cholesterol homeostasis in NAFLD and examine the cellular mechanisms of hepatic FC toxicity and its contribution to ongoing liver injury in this disease. The therapeutic implications of this knowledge are also discussed. © 2015 Elsevier B.V.


Hyland E.M.,Johns Hopkins University | Hyland E.M.,Harvard University | Molina H.,Johns Hopkins University | Molina H.,Center for Genome Regulation | And 10 more authors.
Genes and Development | Year: 2011

The DNA entry and exit points on the nucleosome core regulate the initial invasion of the nucleosome by factors requiring access to the underlying DNA. Here we describe in vivo consequences of eliminating a single proteinDNA interaction at this position through mutagenesis of histone H3 Lys 42 to alanine. This substitution has a dramatic effect on the Saccharomyces cerevisiae transcriptome in both the transcriptional output and landscape of mRNA species produced. We attribute this in part to decreased histone H3 occupancy at transcriptionally active loci, leading to enhanced elongation. Additionally we show that this lysine is methylated in vivo, and genetic studies of methyl-lysine mimics suggest that this modification may be crucial in attenuating gene expression. Interestingly, this site of methylation is unique to Ascomycota, suggesting a recent evolutionary innovation that highlights the evolvability of post-translational modifications of chromatin. © 2011 by Cold Spring Harbor Laboratory Press.


Vazquez M.C.,University of Santiago de Chile | Martinez P.,University of Santiago de Chile | Alvarez A.R.,University of Santiago de Chile | Gonzalez M.,University of Chile | And 4 more authors.
BioMetals | Year: 2012

Niemann-Pick type C disease (NPC) is a hereditary neurovisceral atypical lipid storage disorder produced by mutations in the NPC1 and NPC2 genes. The disease is characterized by unesterified cholesterol accumulation in late endosomal/lysosomal compartments and oxidative stress. Themost affected tissues are the cerebellum and the liver. The lysotropic drug U18666A (U18) has been widely used as a pharmacological model to induce the NPC phenotype in several cell culture lines. It has already been reported that there is an increase in copper content in hepatoma Hu7 cells treated with U18.We confirmed this result with another human hepatoma cell line, HepG2, treatedwithU18 and supplemented with copper in the media. However, in mouse hippocampal primary cultures treated under similar conditions, we did not find alterations in copper content. We previously reported increased copper content in the liver of Npc1-/- mice compared to control animals. Here, we extended the analysis to the copper content in the cerebella, the plasma and the bile ofNPC1 deficientmice.We did not observe a significant change in copper content in the cerebella, whereas we found increased copper content in the plasma and decreased copper levels in the bile of Npc1-/- mice. Finally, we also evaluated the plasma content of ceruloplasmin, and we found an increase in this primary copper-binding protein in Npc1-/- mice. These results indicate cell-type dependence of copper accumulation in NPC disease and suggest that copper transport imbalance may be relevant to the liver pathology observed in NPC disease. © 2012 Springer Science+Business Media, LLC.


PubMed | Hospital Luis Calvo Mackenna, University of Santiago de Chile, University of Cologne, Center for Genome Regulation and 3 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

Niemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients.

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