title: The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.
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 exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Sperber
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Mathieu
authors.affiliation: Department of Biomedical Engineering, Portland, Oregon 97239, USA.|Computational Biology Program, School of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Ferreccio
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Comparative Medicine, University ofWashington, Seattle, Washington 98195, USA.
authors.forename: Jennifer
authors.identifier: http://orcid.org/0000-0001-5685-6279
authors.initials: J
authors.lastname: Hesson
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Zhuojin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Fischer
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Genetic Engineering, SRM University, Kattankulathur 603203, India.
authors.forename: Arikketh
authors.initials: A
authors.lastname: Devi
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Detraux
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Medicine, Division of Medical Genetics and Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Battle
authors.affiliation: University of California Davis Genome Center, California 95616, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Showalter
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Medicine, Division of Medical Genetics and Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Valensisi
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.|Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Bielas
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Nolan G
authors.initials: NG
authors.lastname: Ericson
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Margaretha
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Aaron M
authors.identifier: http://orcid.org/0000-0003-2774-2066
authors.initials: AM
authors.lastname: Robitaille
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Daciana
authors.initials: D
authors.lastname: Margineantu
authors.affiliation: University of California Davis Genome Center, California 95616, USA.|King Abdulaziz University, Faculty of Science, Biochemistry Department, Jeddah21589, Saudi Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hockenbery
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Blau
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA.|Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.affiliation: Department of Biomedical Engineering, Portland, Oregon 97239, USA.|Computational Biology Program, School of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Margolin
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Medicine, Division of Medical Genetics and Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: R David
authors.initials: RD
authors.lastname: Hawkins
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.|Department of Pharmacology, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.|Department of Comparative Medicine, University ofWashington, Seattle, Washington 98195, USA.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Ware
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008745:Methylation; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006657:Histones; D009536:Niacinamide; D012436:S-Adenosylmethionine; D050903:Nicotinamide N-Methyltransferase; D008239:Lysine; C024058:N(1)-methylnicotinamide