Abstract
The naïve epiblast and embryonic stem cells (ESCs) give rise to all cells of the adult. Such developmental plasticity is associated with genome hypomethylation. Here we show that LIF/Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Stat3-/- ESCs show decreased alpha-ketoglutarate production from glutamine, leading to increased Dnmt3a/b expression and DNA methylation. Notably, genome methylation is dynamically controlled by modulating alpha-ketoglutarate availability or Stat3 activation in mitochondria. Alpha-ketoglutarate links metabolism to the epigenome, by reducing the expression of Otx2 and its targets Dnmt3a/b. Genetic inactivation of Otx2 or Dnmt3a/b results in genomic hypomethylation even in the absence of active LIF/Stat3. Stat3-/- ESCs show increased methylation at Imprinting Control Regions and altered expression of cognate transcripts. Single-cell analysis of Stat3-/- embryos confirmed the dysregulated expression of Otx2, Dnmt3a/b and imprinted genes. Several cancers display Stat3-overactivation and abnormal DNA methylation, therefore the molecular module we described might be exploited under pathological conditions.
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