The human endometrium is a dynamic tissue that only is receptive to host the embryo during a brief time in the middle secretory phase, called the window of implantation (WOI). Despite its importance, regulation of the menstrual cycle remains incompletely understood. The aim of this study was to characterize the gene cooperation and regulation of menstrual cycle progression, to dissect the molecular complexity underlying acquisition of endometrial receptivity for a successful pregnancy, and to provide the scientific community with detailed gene co-expression information throughout the menstrual cycle on a user-friendly web-tool database. A retrospective gene co-expression analysis was performed based on the endometrial receptivity array (ERarray) gene signature from 523 human endometrial samples collected across the menstrual cycle, including during the WOI. Gene co-expression analysis revealed the WOI as having the significantly smallest proportion of negative correlations for transcriptional profiles associated with successful pregnancies compared to other cycle stages, pointing to a global transcriptional derepression being involved in acquisition of endometrial receptivity. Regulation was greatest during the transition between proliferative and secretory endometrial phases. Further, we prioritized nuclear hormone receptors as major regulators of this derepression and proved that some genes and transcription factors involved in this process were dysregulated in patients with recurrent implantation failure. We also compiled the wealth of gene co-expression data to stimulate hypothesis-driven single-molecule endometrial studies in a user-friendly database: Menstrual Cycle Gene Co-expression Network (www.menstrualcyclegcn.com). This study revealed a global transcriptional repression across the menstrual cycle, which relaxes when the WOI opens for transcriptional profiles associated with successful pregnancies. These findings suggest that a global transcriptional derepression is needed for embryo implantation and early development.

中文翻译：

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月经周期的转录变化揭示了植入窗口所涉及的分子机制的全局转录抑制

人类子宫内膜是一种动态组织，仅在中间分泌阶段的短暂时间内接受宿主胚胎，称为植入窗口 (WOI)。尽管它很重要，但对月经周期的调节仍未完全了解。本研究的目的是描述基因合作和月经周期进展的调控，剖析获得成功妊娠的子宫内膜容受性的分子复杂性，并为科学界提供整个月经周期的详细基因共表达信息在用户友好的网络工具数据库上。基于从整个月经周期收集的 523 个人类子宫内膜样本的子宫内膜容受性阵列 (ERarray) 基因特征进行回顾性基因共表达分析，包括在 WOI 期间。基因共表达分析显示，与其他周期阶段相比，WOI 与成功怀孕相关的转录谱负相关比例显着最小，这表明全球转录抑制参与了子宫内膜容受性的获得。在增殖期和分泌期子宫内膜之间的过渡期调节最为明显。此外，我们优先考虑将核激素受体作为这种去抑制的主要调节因子，并证明在反复植入失败的患者中，参与这一过程的一些基因和转录因子失调。我们还汇编了丰富的基因共表达数据，以在用户友好的数据库中刺激假设驱动的单分子子宫内膜研究：月经周期基因共表达网络（www.menstrualcyclegcn.com）。这项研究揭示了整个月经周期的全球转录抑制，当 WOI 打开与成功怀孕相关的转录谱时，这种抑制就会放松。这些发现表明，胚胎植入和早期发育需要全局转录抑制。