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      Metabolic Quadrivalency in RSeT Human Embryonic Stem Cells

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          Abstract

          One of the most important properties of human embryonic stem cells (hESCs) is related to their pluripotent states. In our recent study, we identified a previously unrecognized pluripotent state induced by RSeT medium. This state makes primed hESCs resistant to conversion to naïve pluripotent state. In this study, we have further characterized the metabolic features in these RSeT hESCs, including metabolic gene expression, metabolomic analysis, and various functional assays. The commonly reported metabolic modes include glycolysis or both glycolysis and oxidative phosphorylation (i.e., metabolic bivalency) in pluripotent stem cells. However, besides the presence of metabolic bivalency, RSeT hESCs exhibited a unique metabolome with additional fatty acid oxidation and imbalanced nucleotide metabolism. This metabolic quadrivalency is linked to hESC growth independent of oxygen tension and restricted capacity for naïve reprogramming in these cells. Thus, this study provides new insights into pluripotent state transitions and metabolic stress-associated hPSC growth in vitro.

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          Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

          Edward Chen, Christopher M Tan, Yan Kou … (2013)
          Background System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Results Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Conclusions Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr.
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            Autophagy and aging.

            David C. Rubinsztein, Guillermo Mariño, Guido Kroemer (2011)
            Genetic inhibition of autophagy induces degenerative changes in mammalian tissues that resemble those associated with aging, and normal and pathological aging are often associated with a reduced autophagic potential. Pharmacological or genetic manipulations that increase life span in model organisms often stimulate autophagy, and its inhibition compromises the longevity-promoting effects of caloric restriction, Sirtuin 1 activation, inhibition of insulin/insulin growth factor signaling, or the administration of rapamycin, resveratrol, or spermidine. Here, we discuss the probable cause and effect relationship between perturbed autophagy and aging, as well as possible molecular mechanisms that may mediate the anti-aging effects of autophagy. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.

              Christian M Metallo, Paulo A Gameiro, Eric L Bell … (2011)
              Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.
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                Author and article information

                Journal
                Journal ID (nlm-ta): bioRxiv
                Journal ID (publisher-id): BIORXIV
                Title: bioRxiv
                Publisher: Cold Spring Harbor Laboratory
                Publication date (Electronic): 22 February 2024
                Electronic Location Identifier: 2024.02.21.581486
                Affiliations
                [1 ]NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [2 ]Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [3 ]Intramural IT and Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [4 ]Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
                Author notes

                AUTHOR CONTRIBUTIONS

                K.G.C., B.S.M., and P.G.R.: Conceptualization; K.G.C. and B.S.M.: methodology; K.G.C., K.R.J., K.P., D.M., B.S.M: validation and formal analysis; K.G.C., B.S.M.: experimentation and investigation; K.G.C.: writing – original draft; K.G.C., B.S.M., P.G.R.; writing – review and editing; K.G.C.: visualization. All authors approved the final manuscript.

                [* ] Correspondence: cheng@ 123456mail.nih.gov (K.G.C.), barbara.mallon@ 123456nih.gov (B.S.M.)
                Author information
                http://orcid.org/0000-0003-2983-6330
                http://orcid.org/0000-0002-5316-5576
                Article
                DOI: 10.1101/2024.02.21.581486
                PMC ID: 10942463
                PubMed ID: 38496581
                SO-VID: 0a1dd361-aaf3-4f83-8d8f-9dae0ead3773
                License:

                This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

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                Subject: Article

                Keywords: human pluripotent stem cells,pluripotency,rset medium,metabolism,metabolomics,hypoxia,cell proliferation
                Data availability:
                Keywords: human pluripotent stem cells, pluripotency, rset medium, metabolism, metabolomics, hypoxia, cell proliferation

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