Mitochondrial D2HGDH and L2HGDH catalyze the oxidation of D-2-HG and L-2-HG, respectively, into αKG. This contributes to cellular homeostasis in part by modulating the activity of αKG-dependent dioxygenases. Signals that control the expression/activity of D2HGDH/L2HGDH are presumed to broadly influence physiology and pathology. Using cell and mouse models, we discovered that MYC directly induces D2HGDH and L2HGDH transcription. Furthermore, in a manner suggestive of D2HGDH, L2HGDH, and αKG dependency, MYC activates TET enzymes and RNA demethylases, and promotes their nuclear localization. Consistent with these observations, in primary B cell lymphomas MYC expression positively correlated with enhancer hypomethylation and overexpression of lymphomagenic genes. Together, these data provide additional evidence for the role of mitochondria metabolism in influencing the epigenome and epitranscriptome, and imply that in specific contexts wild-type TET enzymes could demethylate and activate oncogenic enhancers.

中文翻译：

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D2HGDH 和 L2HGDH 的 MYC 调节影响表观基因组和表观转录组。

线粒体 D2HGDH 和 L2HGDH 分别催化 D-2-HG 和 L-2-HG 氧化成 αKG。这部分通过调节αKG依赖性双加氧酶的活性来促进细胞稳态。据推测，控制 D2HGDH/L2HGDH 表达/活性的信号广泛影响生理学和病理学。使用细胞和小鼠模型，我们发现 MYC 直接诱导 D2HGDH 和 L2HGDH 转录。此外，以暗示 D2HGDH、L2HGDH 和 αKG 依赖性的方式，MYC 激活 TET 酶和 RNA 去甲基化酶，并促进它们的核定位。与这些观察结果一致，在原发性 B 细胞淋巴瘤中，MYC 表达与增强子低甲基化和淋巴瘤基因的过度表达呈正相关。一起，