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

Nat Cell Biol. 2015 Dec;17(12):1523-35. doi: 10.1038/ncb3264.

Henrik Sperber ¹ ² ³, Julie Mathieu ¹ ², Yuliang Wang ⁴ ⁵, Amy Ferreccio ¹ ², Jennifer Hesson ² ⁶, Zhuojin Xu ², Karin A Fischer ¹ ², Arikketh Devi ¹ ² ⁷, Damien Detraux ¹ ², Haiwei Gu ² ⁸, Stephanie L Battle ² ⁹, Megan Showalter ¹⁰, Cristina Valensisi ² ⁹, Jason H Bielas ¹¹ ¹², Nolan G Ericson ¹¹, Lilyana Margaretha ², Aaron M Robitaille ², Daciana Margineantu ¹¹, Oliver Fiehn ¹⁰ ¹³, David Hockenbery ¹¹, C Anthony Blau ² ¹⁴, Daniel Raftery ² ⁸ ¹¹, Adam A Margolin ⁴ ⁵, R David Hawkins ² ⁹, Randall T Moon ² ¹⁵ ¹⁶, Carol B Ware ² ⁶, Hannele Ruohola-Baker ¹ ²

Affiliations

1 Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
2 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
3 Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
4 Department of Biomedical Engineering, Portland, Oregon 97239, USA.
5 Computational Biology Program, School of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
6 Department of Comparative Medicine, University ofWashington, Seattle, Washington 98195, USA.
7 Department of Genetic Engineering, SRM University, Kattankulathur 603203, India.
8 Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA.
9 Department of Medicine, Division of Medical Genetics and Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
10 University of California Davis Genome Center, California 95616, USA.
11 Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
12 Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
13 King Abdulaziz University, Faculty of Science, Biochemistry Department, Jeddah21589, Saudi Arabia.
14 Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington 98195, USA.
15 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
16 Department of Pharmacology, University of Washington, Seattle, Washington 98109, USA.

PMID: 26571212 DOI: 10.1038/ncb3264

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.

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