Data_Sheet_1_A history of childhood maltreatment is associated with altered DNA methylation levels of DNA methyltransferase 1 in maternal but not neonatal mononuclear immune cells.PDF

Childhood maltreatment (CM) is associated with alterations in DNA methylation (DNAm) especially in stress response genes. Due to the higher risk of overall health complications of individuals with a parental history of CM, intergenerational transmission of CM-associated DNAm changes has been investigated but remains unclear. In this study, we investigated if different severities of CM have any influence on the DNAm of DNA methyltransferase 1 (DNMT1), an important enzyme of the DNAm machinery, in immune and buccal cells of mother-newborn dyads. DNAm was assessed by mass spectrometry using immune cell DNA from mothers (N = 117) and their newborns (N = 113), and buccal cell DNA of mother-newborn dyads (N = 68 each). Mothers with a history of CM had lower mean methylation of DNMT1 in immune cells compared to the mothers without a CM history. CM status only influenced maternal DNMT1 gene expression when at least moderate CM was reported. Buccal cell DNAm was not associated with CM status. Maternal history of CM was not linked to any alterations in DNMT1 mean DNAm in any of the cell types studied in newborns. We conclude that the CM-associated alterations in DNMT1 DNAm might point to allostatic load and can be physiologically relevant, especially in individuals with more severe CM experiences, resulting in an activated DNA methylation machinery that might influence stress response genes. Our lack of significant findings in buccal cells shows the tissue-specific effects of CM on DNAm. In our sample with low to moderate maternal CM history, there was no intergenerational transmission of DNMT1 DNAm in newborns.

童年期虐待（Childhood Maltreatment, CM）与DNA甲基化（DNA Methylation, DNAm）的改变密切相关，尤其在应激反应基因中。鉴于有父母童年期虐待史的个体整体健康并发症风险更高，学界已针对童年期虐待相关DNA甲基化改变的代际传递展开研究，但相关机制仍未明确。本研究以母婴双生子的免疫细胞与颊黏膜细胞为研究对象，探讨不同严重程度的童年期虐待是否会对DNA甲基化机器的关键酶——DNA甲基转移酶1（DNA Methyltransferase 1, DNMT1）的DNA甲基化水平产生影响。研究采用质谱分析法，对母亲（N = 117）及其新生儿（N = 113）的免疫细胞DNA，以及母婴双生子的颊黏膜细胞DNA（每组各N = 68）的DNA甲基化水平进行检测。与无童年期虐待史的母亲相比，有童年期虐待史的母亲其免疫细胞中DNMT1的平均甲基化水平更低。仅当报告的童年期虐待程度至少为中度时，童年期虐待史才会对母亲的DNMT1基因表达产生影响。颊黏膜细胞的DNA甲基化水平与童年期虐待史无显著关联。母亲的童年期虐待史与新生儿所检测的各类细胞中DNMT1的平均DNA甲基化水平改变无关联。本研究结论认为，与童年期虐待相关的DNMT1 DNA甲基化改变可能指向稳态负荷（allostatic load），且具有生理学意义；尤其在经历更严重童年期虐待的个体中，此类改变可激活DNA甲基化机器，进而影响应激反应基因的表达。本研究在颊黏膜细胞中未发现显著关联，这表明童年期虐待对DNA甲基化的影响具有组织特异性。在本研究纳入的母亲童年期虐待史为轻至中度的样本中，未观察到新生儿DNMT1 DNA甲基化水平出现代际传递现象。