Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease.
Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease.
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DOI：
10.1093/eep/dvy010
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发表时间：
2018-04
影响因子：
3.8
通讯作者：
Skinner MK
中科院分区：
文献类型：
--
作者：
Ben Maamar M;Sadler-Riggleman I;Beck D;McBirney M;Nilsson E;Klukovich R;Xie Y;Tang C;Yan W;Skinner MK
乙烯菌核利等有毒物质可引起疾病的表观遗传和表型变异。这种现象可能涉及DNA甲基化、非编码RNA（ncRNA）和组蛋白保留，和/或种系（例如精子）中的修饰。这些不同的表观遗传标记被称为表观突变，可以部分传递跨代表型。本研究旨在研究长春新碱诱导的多种不同表观遗传因素的同时改变，包括大鼠精子中的DNA甲基化、ncRNA和组蛋白保留。妊娠雌性动物（F0代）在胎仔性腺发育期间短暂暴露于乙烯唑啉。研究了直接暴露的F1代胎仔、将产生F2代的胎仔内直接暴露的种系以及跨代F3代精子。DNA甲基化和ncRNA在每代大鼠精子中发生改变，直接暴露F1和F2代与F3代表突变不同。有趣的是，在F3代vinclozolin精子中发现了更多的差异组蛋白保留位点，但在F1或F2代中没有。所有三种不同的表突变类型在乙烯菌核利谱系跨代精子（F3代）中均受到影响。直接暴露世代（F1和F2）的表观遗传学改变与跨代精子表观突变不同。研究了与表观突变相关的基因组特征和基因通路，以帮助阐明这些不同表观遗传过程的整合。我们的研究结果表明，这三种不同类型的表观突变参与和整合在介导的表观遗传的跨代遗传现象。
Epigenetic transgenerational inheritance of disease and phenotypic variation can be induced by several toxicants, such as vinclozolin. This phenomenon can involve DNA methylation, non-coding RNA (ncRNA) and histone retention, and/or modification in the germline (e.g. sperm). These different epigenetic marks are called epimutations and can transmit in part the transgenerational phenotypes. This study was designed to investigate the vinclozolin-induced concurrent alterations of a number of different epigenetic factors, including DNA methylation, ncRNA, and histone retention in rat sperm. Gestating females (F0 generation) were exposed transiently to vinclozolin during fetal gonadal development. The directly exposed F1 generation fetus, the directly exposed germline within the fetus that will generate the F2 generation, and the transgenerational F3 generation sperm were studied. DNA methylation and ncRNA were altered in each generation rat sperm with the direct exposure F1 and F2 generations being distinct from the F3 generation epimutations. Interestingly, an increased number of differential histone retention sites were found in the F3 generation vinclozolin sperm, but not in the F1 or F2 generations. All three different epimutation types were affected in the vinclozolin lineage transgenerational sperm (F3 generation). The direct exposure generations (F1 and F2) epigenetic alterations were distinct from the transgenerational sperm epimutations. The genomic features and gene pathways associated with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. Our results show that the three different types of epimutations are involved and integrated in the mediation of the epigenetic transgenerational inheritance phenomenon.