The prolonged disease state of infertility is associated with embryonic epigenetic dysregulation
The prolonged disease state of infertility is associated with embryonic epigenetic dysregulation
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DOI：
10.1016/j.fertnstert.2021.01.040
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发表时间：
2021-08-03
影响因子：
6.7
通讯作者：
Katz-Jaffe, Mandy G.
中科院分区：
文献类型：
--
作者：
Denomme, Michelle M.;Haywood, Mary E.;Katz-Jaffe, Mandy G.
目的：评价人类整倍体胚泡长期处于不孕症状态的表观遗传学后果。设计：对单个人整倍体胚泡进行甲基化分析和靶向甲基化及表达分析，并与患者的不孕症病程和出生时间相关联。地点：研究。患者(S)：104个剩余的可转移质量的冷冻保存的整倍体胚泡在患者知情的情况下被捐献，并根据怀孕时间进行分组。干预(S)：无主要结果衡量(S)：采用甲基Maxi-Seq平台(ZYMO研究)进行全基因组甲基化检测，而靶向甲基化和表达分析分别通过焦磷酸测序和实时定量聚合酶链式反应进行。统计分析采用学生t检验、单因素方差分析、Fisher精确检验和配对固定再分配随机化检验。结果(S)：对单个胚泡的甲基组分析显示，与生育对照组(0个月)相比，与延长不孕症(>；=60个月)相关的6,609个CpG位点发生了显著变化。显著的CpG改变定位于许多印迹控制区和印迹基因，在差异甲基化的基因中几个信号通路高度表达。靶向印迹甲基化分析发现KvDMR和MEST印迹控制区存在显著的低甲基化，与最小TTP(%24个月)相比，延长TTP(>；=36个月)的基因表达水平显著降低。结论：与单独使用辅助生殖技术相比，不孕症延长的疾病状态与整倍体胚泡中甲基化状态的改变有关，尤其强调基因组印迹调节。(C)2021年，由美国生殖医学学会主办。
Objective: To evaluate the epigenetic consequence of a prolonged disease state of infertility in euploid blastocysts.Design: Methylome analysis as well as targeted imprinted methylation and expression analysis on individual human euploid blastocysts examined in association with duration of patient infertility and time to live birth.Setting: Research study.Patient(s): One hundred four surplus cryopreserved euploid blastocysts of transferrable-quality were donated with informed patient consent and grouped based on time to pregnancy (TTP).Intervention(s): NoneMain Outcome Measure(s): The Methyl Maxi-Seq platform (Zymo Research) was used to determine genome-wide methylation, while targeted methylation and expression analyses were performed by pyrosequencing and quantitative real-time polymerase chain reaction, respectively. Statistical analyses used Student's t test, 1-way ANOVA, Fisher's exact test, and pairwise-fixed reallocation randomization test, where appropriate.Result(s): The methylome analysis of individual blastocysts revealed significant alterations at 6,609 CpG sites associated with prolonged infertility (>= 60 months) compared with those of fertile controls (0 months). Significant CpG alterations were localized to numerous imprinting control regions and imprinted genes, and several signaling pathways were highly represented among genes that were differentially methylated. Targeted imprinting methylation analysis uncovered significant hypomethylation at KvDMR and MEST imprinting control regions, with significant decreases in the gene expression levels upon extended TTP (>= 36 months) compared to minimal TTP (%24 months).Conclusion(s): The prolonged disease state of infertility correlates with an altered methylome in euploid blastocysts, with particular emphasis on genomic imprinting regulation, compared with assisted reproductive technologies alone. (C) 2021 by American Society for Reproductive Medicine.