Department of Genetics Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO 63108, USA; Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St Louis, MO 63108, USA.
Ely and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94115, USA; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA; Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA.
Dev Cell. 2021 May 3;56(9):1238-1252.e5. doi: 10.1016/j.devcel.2021.04.001. Epub 2021 Apr 22.
The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.
人类胎盘及其特化的滋养细胞迅速发育，寿命短暂，控制着妊娠结局，并为后代的健康奠定基础。了解这些行为的分子基础可以为发育和疾病提供信息。在第 2 和第 3 孕期，对胚胎外的表观基因组和转录组进行分析，揭示了 H3K9 三甲基化与深度 DNA 低甲基化区域重叠，基因表达降低，且具有特定区域的模式，阐明了它们的功能。随着妊娠的进展，滋养细胞的 DNA 甲基化增加，基因组上的几个关键组蛋白修饰减少。严重先兆子痫的滋养细胞的 H3K27 乙酰化整体显著增加，在正常足月时下调但在该综合征中上调的基因也上调。此外，一些病例的 H3K27ac 峰呈现不成熟的模式，而另一些则显示出加速衰老的迹象，这表明严重先兆子痫存在特定亚型的改变。因此，滋养细胞的表观基因组在妊娠期间发生显著重编程，胎盘疾病与该过程的失败有关，而 H3K27 高乙酰化是严重先兆子痫的特征。
