GSE134450
Metabolic control of imprinted gene expression in naive pluripotent cells
Naive pluripotent epiblast cells of the preimplantation embryo and their in vitro counterpart, naive murine embryonic stem (ES) cells , are characterised by global DNA hypomethylation. This is caused by elevated expression of TETs oxidases and by downregulation of DNA methyltransferases (DNMTs). However, the signal orchestrating such dynamic changes in vitro and in vivo are only partially understood. Here we report that Stat3 induces genomic hypomethylation via metabolic reconfiguration. In Stat3 -/- ES cells we observed reduced alpha-ketoglutarate (?KG) production from reductive glutaminolysis. This is accompanied by reduced levels of Tet2 and its product, hydroxy-methyl-cytosine, together with increased Dnmt3a/b expression and methyl-cytosine levels. Notably, genome methylation can be dynamically controlled by simply modulating aKG availability, mitochondrial activity or Stat3 activation. Stat3-/- ES cells show also general increased methylation at Imprinting Control Regions accompanied with differential expression of >60% of imprinted genes. Several of them, including Lin28a, Ndn and Peg10, are normally upregulated during differentiation, and displayed anticipated and enhanced expression in Stat3-/- cells, indicating faster differentiation kinetics. Single-cell transcriptome analysis of Stat3-/- embryos confirmed dysregulated expression of Dnmt3a/b, Tet2, imprinted genes and anticipated expression of differentiation markers. Our results reveal that Stat3 bridges the metabolic and epigenetic profiles of naive pluripotent cells and may be relevant under Stat3-dependent pathological conditions. Overall design: Stat3-/- ES cells