@article{c98c6e84ca90471bacb8df6583cacce7,
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.",
author = "Henrik Sperber and Julie Mathieu and Yuliang Wang and Amy Ferreccio and Jennifer Hesson and Zhuojin Xu and Fischer, {Karin A.} and Arikketh Devi and Damien Detraux and Haiwei Gu and Battle, {Stephanie L.} and Megan Showalter and Cristina Valensisi and Bielas, {Jason H.} and Ericson, {Nolan G.} and Lilyana Margaretha and Robitaille, {Aaron M.} and Daciana Margineantu and Oliver Fiehn and David Hockenbery and Blau, {C. Anthony} and Daniel Raftery and Margolin, {Adam A.} and Hawkins, {R. David} and Moon, {Randall T.} and Ware, {Carol B.} and Hannele Ruohola-Baker",
note = "Funding Information: We thank members of the Ruohola-Baker laboratory for helpful discussions throughout this work. We thank D. Djukovic and J. K. Meissen for help with mass spectrometry, D. Jones for help with RNA-seq analysis, W. Zhou, A. Nelson, S. Shannon, S. Sidhu, C. Cavanaugh, Y. Zhang, W. Heath, K. Sankary, E. Engelhart and K. Toor for technical help, K. Au for performing karyotype analysis, A. Madan for performing RNA-seq, P. Treuting for teratoma analysis, K. Bomsztyk (University of Washington, USA) for providing EED antibody, B. Cravatt (Scripps Research Institute, USA) for providing NNMT overexpression constructs and R. Jaenisch (Whitehead Institute for Biomedical Research, USA) and J. Hanna (Weizmann Institute of Science, Israel) for providing WIN1 cells and LIS1 cells, respectively. This work is supported in part by the University of Washington{\textquoteright}s Proteomics Resource (UWPR95794). R.T.M. is an Investigator, and A.M.R. and Z.X. are Associates, of the HHMI. This work was supported by fellowship from the American Heart Association to J.M., AG-NS-0577-09 from the Ellison Medical Foundation for J.H.B., Schultz Fellowship for H.S., grants from the National Institutes of Health 1U24DK097154 for O.F., RO1ES019319 for J.H.B., R01GM097372, R01GM97372-03S1 and R01GM083867 for H.R.-B., 1P01GM081619 for C.A.B., R.T.M., C.B.W., A.M. and H.R.-B., and the NHLBI Progenitor Cell Biology Consortium (U01HL099997; UO1HL099993) for H.R.-B. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",
year = "2015",
month = nov,
day = "27",
doi = "10.1038/ncb3264",
language = "English",
volume = "17",
pages = "1523--1535",
journal = "nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "12",
}