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

Henrik Sperber, Julie Mathieu, Yuliang Wang, Amy Ferreccio, Jennifer Hesson, Zhuojin Xu, Karin A. Fischer, Arikketh Devi, Damien Detraux, Haiwei Gu, Stephanie L. Battle, Megan Showalter, Cristina Valensisi, Jason H. Bielas, Nolan G. Ericson, Lilyana Margaretha, Aaron M. Robitaille, Daciana Margineantu, Oliver Fiehn, David HockenberyC. Anthony Blau, Daniel Raftery, Adam A. Margolin, R. David Hawkins, Randall T. Moon, Carol B. Ware, Hannele Ruohola-Baker

Research output: Contribution to journalArticle

159 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1523-1535
Number of pages13
JournalNature Cell Biology
Volume17
Issue number12
DOIs
StatePublished - Nov 27 2015

ASJC Scopus subject areas

  • Cell Biology

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    Sperber, H., Mathieu, J., Wang, Y., Ferreccio, A., Hesson, J., Xu, Z., Fischer, K. A., Devi, A., Detraux, D., Gu, H., Battle, S. L., Showalter, M., Valensisi, C., Bielas, J. H., Ericson, N. G., Margaretha, L., Robitaille, A. M., Margineantu, D., Fiehn, O., ... Ruohola-Baker, H. (2015). The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nature Cell Biology, 17(12), 1523-1535. https://doi.org/10.1038/ncb3264