Journal Article

Metabolic control of DNA methylation in naive pluripotent cells

Betto, Riccardo M., Guerineau, Vincent, Audano, Matteo, Lauria, Andrea, Boroviak, Thorsten, Perrera, Valentina, Martello, Graziano, Touboul, David, Lohoff, Tim, Arboit, Mattia, Diamante, Linda, Oliviero, Salvatore, Soriano, Maria E., Mitro, Nico, Rigoni, Giovanni, Incarnato, Danny, Rapelli, Stefania, Pedretti, Silvia, Grumati, Paolo, Nichols, Jennifer, Stirparo, Giuliano Giuseppe

2021

Overview

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. Stat3 −/− ESCs 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. Stat3 −/− ESCs show increased methylation at imprinting control regions and altered expression of cognate transcripts. Single-cell analyses of Stat3 −/− embryos 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. Stat3 depletion in pluripotent cells decreases α-ketoglutarate and increases the expression of Otx2 and its targets Dnmt3a and Dnmt3b , leading to global DNA hypermethylation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/1 / 13/100 / 13/95 / 14 / 14/19 / 14/28 / 38 / 38/23 / 38/77 / 631/136/1455 / 631/337/176 / 631/337/2019 / 631/532 / 64 / 64/60 / 96 / 96/106 / Agriculture / Analytical chemistry / Animal Genetics and Genomics / Animals / Biodiversity and Ecology / Biomedical and Life Sciences / Biomedicine / Blastocyst - physiology / Cancer Research / Cell Differentiation / Cells, Cultured / Chemical Sciences / Cheminformatics / Deoxyribonucleic acid / Developmental plasticity / DNA / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA methylation / DNA Methylation - physiology / DNA Methyltransferase 3A / DNA Methyltransferase 3B / Ecotoxicology / Embryo cells / Embryonic Stem Cells - metabolism / Embryonic Stem Cells - physiology / Embryos / Environmental Sciences / Gene expression / Gene Expression Regulation / Gene Function / Genomes / Genomic imprinting / Glutamine / Histones - metabolism / Human Genetics / Inactivation / Ketoglutaric acid / Ketoglutaric Acids - metabolism / Kinases / Leukemia Inhibitory Factor - metabolism / Life Sciences / Mass spectrometry / Metabolism / Metabolites / Mice / Mice, Knockout / Mitochondria / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / or physical chemistry / Other / Otx Transcription Factors - genetics / Otx Transcription Factors - metabolism / Otx2 protein / Phosphorylation / Pluripotency / Pluripotent Stem Cells - metabolism / Promoter Regions, Genetic / Reconfiguration / Scientific imaging / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Stem cells / Theoretical and / Toxicology