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      Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence

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          Abstract

          In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

          DOI: http://dx.doi.org/10.7554/eLife.07836.001

          eLife digest

          Understanding how animals age may help us to prevent age-related or chronic diseases, such as type 2 diabetes and cancer. The tiny nematode worm known as C. elegans is widely used as a model to study aging and has enabled researchers to identify factors that can slow down the aging process. Like other animals, these worms contain female and male sex cells that originate from cells called germline stem cells. The normal lifespan of C. elegans is less than three weeks, but when the germline stem cells are removed, the worms can live for much longer.

          Reproduction requires a lot of energy, which is typically ‘stored’ in molecules of fat. Animals utilize their fat reserves and release this energy by breaking the fat molecules down into smaller molecules as part of their ‘metabolism’. Worms that have had their germline stem cells removed have altered fat metabolism, and it is thought that this may contribute to their increased lifespan. These worms have increased levels of a protein called SKN-1, which alters fat metabolism and helps to protect cells from toxic molecules and other stresses.

          SKN-1 works by regulating the activity (or ‘expression’) of many genes in cells, but it is not clear how this increases the lifespan of the worms. Steinbaugh et al. studied mutant worms that were lacking SKN-1. Unlike normal worms, when the germline stem cells were removed from the mutants, their lifespan did not increase. Further experiments analyzed the genes that are switched on by SKN-1, and identified many that are involved in fat metabolism, in degrading other proteins, and in detoxifying harmful molecules. The experiments also found that SKN-1 reduces the overall amount of fat stored in the body.

          Next, Steinbaugh et al. investigated how SKN-1 stops fat from being stored. During reproduction, cells in the gut produce yolk—which is rich in fats—that will be provided to germ cells to nourish the developing embryo. Worms lacking germline stem cells are not able to reproduce, but they continue to make yolk. Steinbaugh et al. found that the build up of the yolk activates SKN-1, which in turn inhibits the further accumulation of fats.

          Steinbaugh et al.'s findings show that SKN-1 can be activated by fat molecules and plays a direct role in controlling the amount of fat stored in the body of the worms. A future challenge will be to identify the specific fat molecules that activate SKN-1, which could provide a model for understanding how specific fats in human diets could have wide-ranging health benefits.

          DOI: http://dx.doi.org/10.7554/eLife.07836.002

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          DAVID: Database for Annotation, Visualization, and Integrated Discovery.

          Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
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            R: A Language and Environment for Statistical Computing.

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              featureCounts: An efficient general-purpose program for assigning sequence reads to genomic features

              , , (2013)
              Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                2050-084X
                24 August 2015
                2015
                : 4
                : e07836
                Affiliations
                [1 ]deptResearch Division , Joslin Diabetes Center , Boston, United States
                [2 ]deptDepartment of Genetics and Harvard Stem Cell Institute , Harvard Medical School , Boston, United States
                [3 ]deptDepartment of Biomedical Engineering , Boston University , Boston, United States
                Howard Hughes Medical Institute, Stanford University , United States
                Howard Hughes Medical Institute, Stanford University , United States
                Author notes
                [†]

                Research Division, Joslin Diabetes Center, Boston, United States.

                Article
                07836
                10.7554/eLife.07836
                4541496
                26196144
                406f3c8a-e61c-4e72-9478-55e0fd39e746
                © 2015, Steinbaugh et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 31 March 2015
                : 09 July 2015
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK);
                Award ID: NRSA Institutional Postdoctoral Training Grant, T32DK007260
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences (NIGMS);
                Award ID: R01GM062891
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences (NIGMS);
                Award ID: R01GM094398
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: R21AG043949
                Award Recipient :
                Funded by: Myra Reinhard Family Foundation;
                Award ID: Research Award
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK);
                Award ID: Diabetes Research Center Award, P30DK036836
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (NIH);
                Award ID: Office of Research Infrastructure Programs (P40 OD010440)
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Genes and Chromosomes
                Custom metadata
                2.3
                Germ cell ablation delays C. elegans aging, in part, because unconsumed fat triggers activation of the detoxification factor SKN-1/Nrf, which is regulated by lipid signals and maintains lipid homeostasis.

                Life sciences
                aging,fatty acid signaling,germline stem cells,lipid metabolism,proteostasis,skn-1/nrf,c. elegans

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