MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.
MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.
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MYC、线粒体代谢和O-GlcNAc化会聚以调节DNA和RNA脱甲基酶的活性和亚细胞定位。
DOI：
10.1038/s41375-021-01489-7
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发表时间：
2022-04
期刊：
影响因子：
11.4
通讯作者：
Aguiar RCT
中科院分区：
文献类型：
--
作者：
Lin AP;Qiu Z;Ethiraj P;Sasi B;Jaafar C;Rakheja D;Aguiar RCT
线粒体可以作为信号细胞器发挥作用，并且这种输出的一部分导致表观遗传重塑。这一影响深远的相互作用的全部程度仍然没有确定。在这里，我们发现MYC转录激活IDH 2并增加α-酮戊二酸（αKG）水平。该调节步骤诱导α KG依赖性DNA羟化酶和RNA去甲基化酶的活性，从而降低整体DNA和RNA甲基化。MYC还以IDH 2依赖性方式促进TET 1-TET 2-TET 3、FTO和ALKBH 5的核积累。值得注意的是，这种亚细胞运动与MYC以IDH 2依赖性方式的能力相关，并且出乎意料地与αKG直接诱导O-GlcNAc酰化的能力相关。一致地，OGT和OGA（控制这种非典型单糖基化循环的酶）活性的调节在很大程度上概括了MYC-IDH 2-αKG轴对DNA和RNA脱甲基酶亚细胞运动的影响。总之，我们发现了MYC，αKG和O-GlcNAc化之间迄今未被怀疑的串扰，其可能影响表观基因组和表转录组的稳态。
Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.
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DOI：
10.1158/1078-0432.ccr-17-2218
发表时间：
2018-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cooney JD;Lin AP;Jiang D;Wang L;Suhasini AN;Myers J;Qiu Z;Wölfler A;Sill H;Aguiar RCT
通讯作者：
Aguiar RCT
DOI：
10.1158/1078-0432.ccr-11-0770
发表时间：
2011-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kim SW;Rai D;Aguiar RC
通讯作者：
Aguiar RC
影响因子：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
DOI：
10.1016/j.tig.2014.07.005
发表时间：
2014-10
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Huang Y;Rao A
通讯作者：
Rao A
影响因子：
11.4
作者：
Golks, Alexander;Tran, Thi-Thanh Thao;Guerini, Danilo
通讯作者：
Guerini, Danilo