OBJECTIVE To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve. DESIGN Prospectively collected material from a multicenter cohort of women undergoing fertility treatment. SETTING Private and university-based facilities for clinical services and research. PATIENT(S) One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations. RESULT(S) Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485). CONCLUSION(S) The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.

中文翻译：

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在卵巢储备减少的女性中鉴定独特的表观遗传特征

目的 研究卵巢储备减少 (DOR) 女性的壁颗粒细胞 (MGC) 和白细胞的表观遗传特征是否与卵巢储备正常或高的女性不同。设计 从接受生育治疗的多中心女性队列中前瞻性收集材料。设置用于临床服务和研究的私人和大学设施。患者 119 名不同年龄和卵巢储备状态（抗苗勒管激素水平）的女性提供了血液样本和 MGC。干预措施 无。主要结果测量从全基因组甲基化阵列数据测量表观遗传老化率：DNA 甲基化变异性、年龄加速、DNA 甲基化端粒长度估计 (DNAmTL) 和表观突变的积累。结果 DOR 或高卵巢储备样本与对照（正常卵巢储备）的比较显示 DOR 和正常样本之间的差异甲基化变异性，MGC 中有 4,199 个 CpG，高和正常之间有 447 个（错误发现率 < 0.05）。来自 DOR 的 MGC 中的可变位点在标记有抑制性组蛋白修饰 H3K27me3 的区域中富集，还包括参与卵泡发生的基因，如胰岛素生长因子 2 (IGF2) 和抗苗勒管激素 (AMH)。不管卵巢储备如何，在白细胞中检测到的信号很少，并且没有发现与 MGC 中的信号重叠。此外，我们发现 DOR 女性的 MGC 表观突变数量更多（Kruskal-Wallis 检验，平均值差异 = 3,485）。结论 (S) 在患有 DOR 的女性中，人类卵泡的体细胞具有独特的表观遗传特征。高频率的表观突变表明过早衰老。白细胞表观遗传谱中未反映卵巢储备状态。