DNMT3B deficiency alters mitochondrial biogenesis and α‐ketoglutarate levels in human embryonic stem cells

Human embryonic stem cells deficient for DNMT3B exhibit increased expression of isocitrate dehydrogenases and buildup of α‐ketoglutarate. In addition, loss of DNMT3B disrupts the cells mitochondrial fusion and fission balance, reduces mitochondrial DNA levels, and elicits a switch from glycolysis to oxidative phosphorylation. AbstractEmbryonic stem cell (ESC) renewal and differentiation is regulated by metabolites that serve as co ‐factors for epigenetic enzymes. Increase of α‐ketoglutarate (α‐KG), a co‐factor for histone and DNA demethylases, triggers multi‐lineage differentiation in human ESCs. To gain further insight how the metabolic fluxes in pluripotent stem cells can be influenced by inactivating mutations in epigenetic enzymes, we generated human ESCs deficient forde novo DNA methyltransferases (DNMT) 3A and 3B. Our data reveal a bidirectional dependence between DNMT3B and α‐KG levels: a‐KG is significantly upregulated in cells deficient for DNMT3B, while DNMT3B expression is downregulated in human ESCs treated with α‐KG. In addition, DNMT3B null human ESCs exhibit a disturbed mitochondrial fission and fusion balance and a switch from glycolysis to oxidative p hosphorylation. Taken together, our data reveal a novel link between DNMT3B and the metabolic flux of human ESCs.© AlphaMed Press 2020Significance StatementThe current study reveals a novel link between DNMT3B and the metabolic flux in human ESCs. Loss of DNMT3B disrupts the cells mitocho...

Source: Stem Cells - July 10, 2020 Category: Stem Cells Authors: Artur Cieslar ‐Pobuda, Theresa D. Ahrens, Safak Caglayan, Sidney Behringer, Luciana Hannibal, Judith Staerk Tags: Embryonic Stem Cells/Induced Pluripotent Stem Cells Source Type: research