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.
While previous studies have revealed the importance of Wnt and HIF pathways in naïve or primed pluripotent stem cells34,38,42–44, we now show that these pathways are regulated by metabolite levels. We propose that the availability of SAM triggers the cascade by activating PRC2 and thereby increasing repressive H3K27me3 epigenetic marks in the promoters of key regulators of naïve to primed transition, HIF repressor and Wnt ligands (Fig.8J). These studies pave the way for further understanding and utilization of metabolite specific molecular mechanisms for cell fate changes in general.
These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.
Citation & Full Text
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., Valensis, C., Bielas, J.H., Ericson, N.G., Margaretha, L., Robitaille, A.M., Margineantu, D., Fiehn, O., Hockenbery, D., Blau, C.A., Raftery, D., Margolin, A., Hawkins, R.D., Moon, R.T., Ware, C.B., and Ruohola-Baker, H.: The Metabolic Enzyme, Nicotinamide N-Methyltransferase Regulates the Epigenetic Landscape during Naïve to Primed Human Embryonic Stem Cell Transition, Nature Cell Biol. 17:1523-1535, 2015.