Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 3DY, UK.
Development. 2020 Mar 17;147(6):dev185629. doi: 10.1242/dev.185629.
Reproductive decline in older female mice can be attributed to a failure of the uterus to decidualise in response to steroid hormones. Here, we show that normal decidualisation is associated with significant epigenetic changes. Notably, we identify a cohort of differentially methylated regions (DMRs), most of which gain DNA methylation between the early and late stages of decidualisation. These DMRs are enriched at progesterone-responsive gene loci that are essential for reproductive function. In female mice nearing the end of their reproductive lifespan, DNA methylation fidelity is lost at a number of CpG islands (CGIs) resulting in CGI hypermethylation at key decidualisation genes. Importantly, this hypermethylated state correlates with the failure of the corresponding genes to become transcriptionally upregulated during the implantation window. Thus, age-associated DNA methylation changes may underlie the decidualisation defects that are a common occurrence in older females. Alterations to the epigenome of uterine cells may therefore contribute significantly to the reproductive decline associated with advanced maternal age.
老年雌性小鼠的生殖能力下降可归因于子宫对甾体激素反应的蜕膜化失败。在这里，我们表明正常的蜕膜化与显著的表观遗传变化有关。值得注意的是，我们确定了一组差异甲基化区域 (DMR)，其中大多数在蜕膜化的早期和晚期之间获得 DNA 甲基化。这些 DMR 富集在孕激素反应基因座，这些基因座对生殖功能至关重要。在接近生殖寿命末期的雌性小鼠中，一些 CpG 岛 (CGI) 的 DNA 甲基化保真度丧失，导致关键蜕膜化基因的 CGI 过度甲基化。重要的是，这种超甲基化状态与相应基因在着床窗口期间转录上调失败相关。因此，与年龄相关的 DNA 甲基化变化可能是老年女性中常见的蜕膜化缺陷的基础。因此，子宫细胞的表观基因组改变可能会极大地导致与高龄相关的生殖能力下降。
