Metabolic control of DNA methylation in naive pluripotent cells

Feb 2, 2021Nature genetics

How metabolism influences DNA methylation in early stem cells

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Abstract

LIF-Stat3 signaling induces genomic hypomethylation through metabolic changes.

Genomic hypomethylation is linked to changes in metabolism, specifically through α-ketoglutarate levels.
Increased expression of the genes Dnmt3a and Dnmt3b is associated with decreased α-ketoglutarate production from glutamine.
Availability of α-ketoglutarate or activation of Stat3 can dynamically control genome methylation.
Genetic inactivation of Otx2 or Dnmt3a and Dnmt3b leads to genomic hypomethylation independently of LIF-Stat3 signaling.
Increased methylation at imprinting control regions and altered expression of related transcripts are observed in Stat3ESCs.
Single-cell analyses of Stat3embryos reveal dysregulated expression of genes associated with genomic methylation.

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Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF-Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Stat3ESCs show decreased α-ketoglutarate production from glutamine, leading to increased Dnmt3a and Dnmt3b expression and DNA methylation. Notably, genome methylation is dynamically controlled through modulation of α-ketoglutarate availability or Stat3 activation in mitochondria. Alpha-ketoglutarate links metabolism to the epigenome by reducing the expression of Otx2 and its targets Dnmt3a and Dnmt3b. Genetic inactivation of Otx2 or Dnmt3a and Dnmt3b results in genomic hypomethylation even in the absence of active LIF-Stat3. Stat3ESCs show increased methylation at imprinting control regions and altered expression of cognate transcripts. Single-cell analyses of Stat3embryos confirmed the dysregulated expression of Otx2, Dnmt3a and Dnmt3b as well as imprinted genes. Several cancers display Stat3 overactivation and abnormal DNA methylation; therefore, the molecular module that we describe might be exploited under pathological conditions. -/--/--/-

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Metabolic control of DNA methylation in naive pluripotent cells

Abstract

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