DNMT3B deficiency alters mitochondrial biogenesis and α-ketoglutarate levels in human embryonic stem cells,STEM CELLS

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DNMT3B deficiency alters mitochondrial biogenesis and α-ketoglutarate levels in human embryonic stem cells
STEM CELLS ( IF 4.0 ) Pub Date : 2020-07-20 , DOI: 10.1002/stem.3256
Artur Cieslar-Pobuda _{1,

2} , Theresa D Ahrens ₁ , Safak Caglayan ₁ , Sidney Behringer ₃ , Luciana Hannibal ₃ , Judith Staerk _{1,

4}

Affiliation

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.

中文翻译：

DNMT3B 缺陷改变人胚胎干细胞中的线粒体生物合成和 α-酮戊二酸水平

胚胎干细胞的更新和分化受到作为表观遗传酶辅助因子的代谢物的调节。 α-酮戊二酸 (α-KG)（组蛋白和 DNA 去甲基酶的辅助因子）的增加会触发人胚胎干细胞 (hESC) 的多谱系分化。为了进一步了解多能干细胞中的代谢通量如何受到表观遗传酶失活突变的影响，我们生成了缺乏从头 DNA 甲基转移酶 (DNMT) 3A 和 3B 的 hESC。我们的数据揭示了 DNMT3B 和 α-KG 水平之间的双向依赖性：在 DNMT3B 缺陷的细胞中，a-KG 显着上调，而在用 α-KG 处理的 hESC 中，DNMT3B 表达下调。此外，DNMT3B null hESC 表现出线粒体裂变和融合平衡紊乱以及从糖酵解到氧化磷酸化的转变。综上所述，我们的数据揭示了 DNMT3B 与 hESC 代谢通量之间的新联系。

更新日期：2020-07-20

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