For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
57
views
37
references
 Top references
cited by
169
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      782
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans display two stable yet epigenetically distinct states of pluripotency, naïve and primed. We now show that nicotinamide-N-methyl transferase (NNMT) and metabolic state regulate pluripotency in hESCs. Specifically, in naïve hESCs NNMT and its enzymatic product 1-methylnicotinamide (1-MNA) are highly upregulated, and NNMT is required for low SAM levels and H3K27me3 repressive state. NNMT consumes SAM in naïve cells, making it unavailable for histone methylation that represses Wnt and activates HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.

          Related collections

          Most cited references37

          • Record: found
          • Abstract: found
          • Article: not found

          HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia.

          Edurne Berra, Emmanuel Benizri, Amandine Ginouves … (2003)
          Hypoxia-inducible factor (HIF), a transcriptional complex conserved from Caenorhabditis elegans to vertebrates, plays a pivotal role in cellular adaptation to low oxygen availability. In normoxia, the HIF-alpha subunits are targeted for destruction by prolyl hydroxylation, a specific modification that provides recognition for the E3 ubiquitin ligase complex containing the von Hippel-Lindau tumour suppressor protein (pVHL). Three HIF prolyl-hydroxylases (PHD1, 2 and 3) were identified recently in mammals and shown to hydroxylate HIF-alpha subunits. Here we show that specific 'silencing' of PHD2 with short interfering RNAs is sufficient to stabilize and activate HIF-1alpha in normoxia in all the human cells investigated. 'Silencing' of PHD1 and PHD3 has no effect on the stability of HIF-1alpha either in normoxia or upon re-oxygenation of cells briefly exposed to hypoxia. We therefore conclude that, in vivo, PHDs have distinct assigned functions, PHD2 being the critical oxygen sensor setting the low steady-state levels of HIF-1alpha in normoxia. Interestingly, PHD2 is upregulated by hypoxia, providing an HIF-1-dependent auto-regulatory mechanism driven by the oxygen tension.
          Article 0 comments Cited 333 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells

            Edward J. Grow, Ryan Flynn, Shawn L. Chavez … (2015)
            Summary Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, which comprise nearly 8% of the human genome 1 . The most recently acquired human ERV is HERV-K (HML-2), which repeatedly infected the primate lineage both before and after the divergence of humans and chimpanzees 2,3 . Unlike most other human ERVs, HERV-K retained multiple copies of intact open reading frames (ORFs) encoding retroviral proteins 4 . However, HERV-K is transcriptionally silenced by the host with exception of certain pathological contexts, such as germ cell tumors, melanoma, or HIV infection 5–7 . Here we demonstrate that DNA hypomethylation at LTR elements representing the most recent genomic integrations, together with transactivation by OCT4, synergistically facilitate HERV-K expression. Consequently, HERV-K is transcribed during normal human embryogenesis beginning with embryonic genome activation (EGA) at the 8-cell stage, continuing through the emergence of epiblast cells in pre-implantation blastocysts, and ceasing during hESC derivation from blastocyst outgrowths. Remarkably, HERV-K viral-like particles and Gag proteins are detected in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, HERV-K accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERV-K can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, arguing that complex interactions between retroviral proteins and host factors can fine-tune regulatory properties of early human development.
            Article 0 comments Cited 278 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition.

              Wenyu Zhou, Michael Choi, Daciana Margineantu … (2012)
              The function of metabolic state in stemness is poorly understood. Mouse embryonic stem cells (ESC) and epiblast stem cells (EpiSC) are at distinct pluripotent states representing the inner cell mass (ICM) and epiblast embryos. Human embryonic stem cells (hESC) are similar to EpiSC stage. We now show a dramatic metabolic difference between these two stages. EpiSC/hESC are highly glycolytic, while ESC are bivalent in their energy production, dynamically switching from glycolysis to mitochondrial respiration on demand. Despite having a more developed and expanding mitochondrial content, EpiSC/hESC have low mitochondrial respiratory capacity due to low cytochrome c oxidase (COX) expression. Similarly, in vivo epiblasts suppress COX levels. These data reveal EpiSC/hESC functional similarity to the glycolytic phenotype in cancer (Warburg effect). We further show that hypoxia-inducible factor 1α (HIF1α) is sufficient to drive ESC to a glycolytic Activin/Nodal-dependent EpiSC-like stage. This metabolic switch during early stem-cell development may be deterministic.
              Article 0 comments Cited 231 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 8 October 2015
                Publication date (Electronic): 16 November 2015
                Publication date (Print): December 2015
                Publication date PMC-release: 01 June 2016
                Volume: 17
                Issue: 12
                Pages: 1523-1535
                Affiliations
                [1 ]Department of Biochemistry, Seattle, WA
                [2 ]Institute for Stem Cell and Regenerative Medicine, Seattle, WA
                [3 ]Department of Chemistry, University of Washington, Seattle, WA
                [4 ]Sage Bionetworks, Seattle, WA
                [5 ]Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR
                [6 ]Department of Genetic Engineering, SRM University, Kattankulathur, India
                [7 ]Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, CA
                [8 ]Department of Medicine, Division of Medical Genetics and Department of Genome Sciences, University of Washington, CA
                [9 ]University of California Davis Genome Center, CA
                [10 ]Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                [11 ]Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA
                Author notes
                Correspondence: Hannele Ruohola-Baker hannele@ 123456uw.edu
                [*]

                equal contribution

                Article
                Manuscript ID: NIHMS727862
                DOI: 10.1038/ncb3264
                PMC ID: 4662931
                PubMed ID: 26571212
                SO-VID: dafa29ee-5571-44e8-8210-e3c787f2ab21
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

                Comments

                Comment on this article

                scite_

                Similar content782

                See all similar

                Cited by163

                See all cited by

                Most referenced authors1,786

                See all reference authors