Altering metabolism programs cell identity via NAD+ dependent deacetylation

Cells change their metabolic profiles in response to an underling gene regulatory network, but how can alterations in metabolism encode specific transcriptional instructions? Here we show that forcing metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the mammalian blastocyst in cultures we refer to as enhanced metabolic ESCs (EMESCs). The creation of EMESCs depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS), that in turns activates NAD+-dependent deacetlylases of the Sirtuin family. The activation of this pathway leads to the deacetylation of histones and key transcription factors leading to a revised ICM-like gene regulatory network. The exploitation of the NAD+/NADH coenzyme normally coupled to elevated OXPHOS to program lineage specific transcription suggests new paradigms for how cells respond to alterations in their environment.