Kurasz Karolina, Rzeszowska-Wolny Joanna, Oliński Ryszard, Foksiński Marek, Fujarewicz Krzysztof
Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karlowicza 24, 85-092 Bydgoszcz, Poland.
Epigenomes. 2024 May 2;8(2):18. doi: 10.3390/epigenomes8020018.
In living cells, some reactions can be conducted by more than one enzyme and sometimes it is difficult to establish which enzyme is responsible. Such is the case with proteins from the TET family, capable of converting 5-methyl-2'-deoxycytidine (5-mdC) in DNA to 5-(hydroxymethyl)-2'-deoxycytidine (5-hmdC) and further to 5-formyl-2'-deoxycytidine (5-fdC) and 5-carboxy-2'-deoxycytidine (5-cadC). The estimation of the efficiency of particular TETs in particular oxidative reactions and different cell types is important but experimentally difficult. Here, we propose an approach with mathematical modeling in which methylation and known deoxycytidine modification pathways are presented by 343 possible model versions with assumed different combinations of TET1, 2, and 3 activities in different pathways. Model parameters were calculated on the basis of 5-mdC, 5-hmdC, 5-fdC, 5-cadC, and 5-hmdU levels experimentally assessed in five human cultured cell lines and previously published. Selection of the model versions that give in simulations the best average fit to experimental data suggested that not all TET proteins participate in all modification reactions and that TET3 activity may be especially important in the reaction of 5-fdC removal.
在活细胞中，一些反应可以由多种酶进行，有时很难确定是哪种酶起作用。TET家族的蛋白质就是这种情况，它们能够将DNA中的5-甲基-2'-脱氧胞苷（5-mdC）转化为5-（羟甲基）-2'-脱氧胞苷（5-hmdC），并进一步转化为5-甲酰基-2'-脱氧胞苷（5-fdC）和5-羧基-2'-脱氧胞苷（5-cadC）。评估特定TET蛋白在特定氧化反应和不同细胞类型中的效率很重要，但在实验上却很困难。在这里，我们提出一种数学建模方法，其中甲基化和已知的脱氧胞苷修饰途径由343种可能的模型版本表示，这些模型假设了不同途径中TET1、2和3活性的不同组合。模型参数是根据在五种人类培养细胞系中实验评估并已发表的5-mdC、5-hmdC、5-fdC、5-cadC和5-hmdU水平计算得出的。选择在模拟中与实验数据平均拟合最佳的模型版本表明，并非所有TET蛋白都参与所有修饰反应，并且TET3活性在5-fdC去除反应中可能尤为重要。
