Siddeek Bénazir, Lakhdari Nadjem, Inoubli Lilia, Paul-Bellon Rachel, Isnard Véronique, Thibault Emmanuelle, Bongain André, Chevallier Daniel, Repetto Emanuela, Trabucchi Michele, Michiels Jean-François, Yzydorczyk Catherine, Simeoni Umberto, Urtizberea Michel, Mauduit Claire, Benahmed Mohamed
Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.
Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.
Epigenomics. 2016 Nov;8(11):1459-1479. doi: 10.2217/epi-2016-0061. Epub 2016 Oct 20.
The Developmental Origin of Health and Disease refers to the concept that early exposure to toxicants or nutritional imbalances during perinatal life induces changes that enhance the risk of developing noncommunicable diseases in adulthood. Patients/materials & methods: An experimental model with an adult chronic germ cell death phenotype resulting from exposure to a xenoestrogen was used.
A reciprocal negative feedback loop involving decreased EZH2 protein level and increased miR-101 expression was identified. In vitro and in vivo knockdown of EZH2 induced an apoptotic process in germ cells through increased levels of apoptotic factors (BIM and BAD) and DNA repair alteration via topoisomerase 2B deregulation. The increased miR-101 levels were observed in the animal blood, meaning that miR-101 may be a part of a circulating mark of germ cell death.
miR-101-EZH2 pathway deregulation could represent a novel pathophysiological epigenetic basis for adult germ cell disease with environmental and developmental origins.
健康与疾病的发育起源指的是这样一种概念，即在围产期生命早期接触毒物或营养失衡会引发一些变化，从而增加成年后患非传染性疾病的风险。患者/材料与方法：使用了一个因接触外源性雌激素而导致成年慢性生殖细胞死亡表型的实验模型。
确定了一个涉及EZH2蛋白水平降低和miR-101表达增加的相互负反馈回路。在体外和体内敲低EZH2通过增加凋亡因子（BIM和BAD）水平以及通过拓扑异构酶2B失调改变DNA修复，从而诱导生殖细胞发生凋亡过程。在动物血液中观察到miR-101水平升高，这意味着miR-101可能是生殖细胞死亡循环标志物的一部分。
miR-101-EZH2通路失调可能是具有环境和发育起源的成年生殖细胞疾病的一种新的病理生理表观遗传基础。
