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

H Sperber, J Mathieu, Y Wang, A Ferreccio… - Nature cell …, 2015 - nature.com
H Sperber, J Mathieu, Y Wang, A Ferreccio, J Hesson, Z Xu, KA Fischer, A Devi, D Detraux…
Nature cell biology, 2015nature.com
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 …
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.
nature.com