Van de Pette Mathew, Abbas Allifia, Feytout Amelie, McNamara Gráinne, Bruno Ludovica, To Wilson K, Dimond Andrew, Sardini Alessandro, Webster Zoe, McGinty James, Paul Eleanor J, Ungless Mark A, French Paul M W, Withers Dominic J, Uren Anthony, Ferguson-Smith Anne C, Merkenschlager Matthias, John Rosalind M, Fisher Amanda G
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Photonics Group, Department of Physics, Blackett Laboratory, Imperial College London, London SW7 2AZ, UK.
Cell Rep. 2017 Jan 31;18(5):1090-1099. doi: 10.1016/j.celrep.2017.01.010.
Imprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility. Here, we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1c expression in mice and showed that expression was modulated by environmental factors encountered in utero. Acute exposure to chromatin-modifying drugs resulted in de-repression of paternally inherited (silent) Cdkn1c alleles in embryos that was temporary and resolved after birth. In contrast, deprivation of maternal dietary protein in utero provoked permanent de-repression of imprinted Cdkn1c expression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss. Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early-life adversity to later-life outcomes. Furthermore, Cdkn1c-luciferase mice offer non-invasive tools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.
印记基因根据亲本来源进行调控，可影响胚胎生长和代谢，并赋予疾病易感性。在此，我们设计了灵敏的等位基因特异性报告基因，以非侵入性方式监测小鼠中印记的Cdkn1c表达，并表明其表达受子宫内所接触的环境因素调节。急性暴露于染色质修饰药物会导致胚胎中父本遗传（沉默）的Cdkn1c等位基因去抑制，这种去抑制是暂时的，出生后即恢复。相反，子宫内母体膳食蛋白质缺乏会引发印记的Cdkn1c表达的永久性去抑制，这种去抑制持续至成年期，并且是通过叶酸依赖的DNA甲基化丢失机制发生的。鉴于印记基因在调节成年个体行为和代谢过程中的作用，这些结果确立了印记失调是一种将早期生活逆境与后期生活结局联系起来的可靠机制。此外，Cdkn1c-荧光素酶小鼠提供了非侵入性工具，以识别破坏表观遗传过程的因素以及限制其长期影响的策略。
