Lack of Major Genome-Wide DNA Methylation Changes in Succinate-Treated Human Epithelial Cells.
Lack of Major Genome-Wide DNA Methylation Changes in Succinate-Treated Human Epithelial Cells.
复制标题
DOI：
10.3390/ijms23105663
复制
发表时间：
2022-05-18
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
三羧酸(TCA)的代谢物琥珀酸是一种竞争性的双加氧酶抑制剂，需要α-酮戊二酸作为辅因子。其中一个双加氧酶家族是Tet蛋白，它氧化5-甲基胞嘧啶以促进DNA去甲基化。抑制DNA去甲基化预计会导致DNA超甲基化，至少在参与Tet蛋白的基因组区域是这样。我们用琥珀酸处理人支气管上皮细胞五天，通过观察Tet酶反应的第一个氧化产物5-羟甲基胞嘧啶的减少来证实它对Tet蛋白功能的影响。然后，我们通过进行全基因组亚硫酸氢盐测序，分析了全球DNA甲基化模式。出乎意料的是，我们没有观察到达到全基因组统计意义的差异甲基化区域(DMR)。我们观察到一些聚集的DNA低甲基化区域，这也是基于所提出的机制所预期的。我们讨论了我们观察到的可能的解释，以及这些发现对肿瘤发生的影响。
The tricarboxylic acid (TCA) metabolite, succinate, is a competitive inhibitor of dioxygenase enzymes that require alpha ketoglutarate as a cofactor. One family of dioxygenases are the ten-eleven translocation (TET) proteins, which oxidize 5-methylcytosine to promote DNA demethylation. Inhibition of DNA demethylation is expected to lead to DNA hypermethylation, at least at genomic regions at which TET proteins are engaged. We treated human bronchial epithelial cells with succinate for five days and confirmed its effect on TET protein function by observing diminished formation of 5-hydroxymethylcytosine, the first oxidation product of the TET enzymatic reaction. We then analyzed global DNA methylation patterns by performing whole-genome bisulfite sequencing. Unexpectedly, we did not observe differentially methylated regions (DMRs) that reached genome-wide statistical significance. We observed a few regions of clustered DNA hypomethylation, which was also not expected based on the proposed mechanisms. We discuss potential explanations for our observations and the implications of these findings for tumorigenesis.
登录
查看更多内容
影响因子：
3.9
作者：
Edwards JR;Yarychkivska O;Boulard M;Bestor TH
通讯作者：
Bestor TH
影响因子：
14.9
作者：
Jin SG;Kadam S;Pfeifer GP
通讯作者：
Pfeifer GP
影响因子：
3.6
作者：
Pfeifer, Gerd P.;Xiong, Wenying;Hahn, Maria A.;Jin, Seung-Gi
通讯作者：
Jin, Seung-Gi
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A