Pal Anandita, Oakes Judy, Elnagheeb Marwa, Ideraabdullah Folami Y
Department of Nutrition, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.
Epigenet Insights. 2020 Dec 2;13:2516865720970575. doi: 10.1177/2516865720970575. eCollection 2020.
Deficiency of methyl donor nutrients folate, choline, and methionine (methyl deficiency) during gestation can impair fetal development and perturb DNA methylation. Here, we assessed genetic susceptibility to methyl deficiency by comparing effects in wildtype C57BL/6J (B6) mice to mutant mice carrying a 1.3 kb deletion at the Imprinting Control Region (ICR) ( ). The mutation mimics microdeletions observed in Beckwith-Wiedemann syndrome (BWS) patients, who exhibit epimutations in that cause loss of imprinting and fetal overgrowth. Dams were treated during pregnancy with 1 of 4 methyl sufficient (MS) or methyl deficient (MD) diets, with or without the antibiotic commonly used to deplete folate producing gut microbes. As expected, after ~9 weeks of treatment, dams in MD and MD + antibiotic groups exhibited substantially reduced plasma folate concentrations. mutant lines were more susceptible to adverse pregnancy outcomes caused by methyl deficiency (reduced birth rate and increased pup lethality) and antibiotic (decreased litter size and litter survival). Surprisingly, pup growth/development was only minimally affected by methyl deficiency, while antibiotic treatment caused inverse effects on B6 and lines. B6 pups treated with antibiotic exhibited increased neonatal and weanling bodyweight, while both wildtype and mutant pups of heterozygous dams exhibited decreased neonatal bodyweight that persisted into adulthood. Interestingly, only antibiotic-treated pups carrying the mutation exhibited altered DNA methylation at the ICR, suggesting ICR epimutation was not sufficient to explain the altered phenotypes. These findings demonstrate that genetic mutation of the ICR increases offspring susceptibility to developmental perturbation in the methyl deficiency model, maternal and pup genotype play an essential role, and antibiotic treatment in the model also plays a key independent role.
孕期甲基供体营养素叶酸、胆碱和蛋氨酸缺乏（甲基缺乏）会损害胎儿发育并扰乱DNA甲基化。在此，我们通过比较野生型C57BL/6J（B6）小鼠与在印记控制区域（ICR）携带1.3 kb缺失的突变小鼠的效应，评估了对甲基缺乏的遗传易感性。该突变模拟了在贝克威思-维德曼综合征（BWS）患者中观察到的微缺失，这些患者在IGF2中表现出表观突变，导致印记丢失和胎儿过度生长。在孕期，母鼠接受4种甲基充足（MS）或甲基缺乏（MD）饮食中的一种处理，有或没有用于消耗产生叶酸的肠道微生物的抗生素。如预期的那样，经过约9周的处理后，MD和MD +抗生素组的母鼠血浆叶酸浓度大幅降低。Kcnq1ot1突变系对甲基缺乏（出生率降低和幼崽死亡率增加）和抗生素（窝仔数和窝仔存活率降低）引起的不良妊娠结局更敏感。令人惊讶的是，幼崽生长/发育仅受到甲基缺乏的轻微影响，而抗生素处理对B6和Kcnq1ot1系产生相反的影响。用抗生素处理的B6幼崽表现出新生儿和断奶时体重增加，而异质型Kcnq1ot1母鼠的野生型和突变型幼崽均表现出新生儿体重降低，这种情况持续到成年期。有趣的是，只有携带Kcnq1ot1突变的经抗生素处理的幼崽在ICR处表现出DNA甲基化改变，表明ICR表观突变不足以解释改变的表型。这些发现表明，ICR的基因突变增加了甲基缺乏模型中后代对发育扰动的易感性，母鼠和幼崽基因型起着至关重要的作用，并且该模型中的抗生素处理也起着关键的独立作用。
