Open AccessDNMT3B deficiency alters mitochondrial biogenesis and α‐ketoglutarate levels in human embryonic stem cells
Author(s) -
CieslarPobuda Artur,
Ahrens Theresa D.,
Caglayan Safak,
Behringer Sidney,
Hannibal Luciana,
Staerk Judith
Publication year - 2020
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.3256
Subject(s) - biology , embryonic stem cell , microbiology and biotechnology , stem cell , epigenetics , dnmt3b , methyltransferase , induced pluripotent stem cell , cellular differentiation , genetics , methylation , dna , gene
Embryonic stem cell renewal and differentiation is regulated by metabolites that serve as cofactors for epigenetic enzymes. An increase of α‐ketoglutarate (α‐KG), a cofactor for histone and DNA demethylases, triggers multilineage differentiation in human embryonic stem cells (hESCs). To gain further insight into how the metabolic fluxes in pluripotent stem cells can be influenced by inactivating mutations in epigenetic enzymes, we generated hESCs deficient for de novo DNA methyltransferases (DNMTs) 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 hESCs treated with α‐KG. In addition, DNMT3B null hESCs exhibit a disturbed mitochondrial fission and fusion balance and a switch from glycolysis to oxidative phosphorylation. Taken together, our data reveal a novel link between DNMT3B and the metabolic flux of hESCs.