The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization.
The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization.
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DOI：
10.1371/journal.pgen.1005937
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发表时间：
2016-04
期刊：
影响因子：
4.5
通讯作者：
Lydon JP
中科院分区：
文献类型：
--
作者：
Kommagani R;Szwarc MM;Vasquez YM;Peavey MC;Mazur EC;Gibbons WE;Lanz RB;DeMayo FJ;Lydon JP
黄体酮通过孕酮受体 (PGR) 对子宫内膜基质细胞蜕膜化至关重要，蜕膜化是一种细胞转化事件，基质成纤维细胞分化为蜕膜细胞。子宫蜕膜化支持胚胎植入和胎盘以及后续事件，共同确保成功妊娠。因此，蜕膜化受损不仅会导致着床失败或胎儿早期流产，还可能导致所有三个妊娠期的潜在不良后果。全基因组范围内的转录重编程是人类子宫内膜基质细胞（hESC）黄体酮依赖性蜕膜化的基础。然而，对这些全局转录变化编码的功能必需信号的识别仍然不完整。重要的是，这种知识差距削弱了未来改善基于功能失调的子宫内膜的植入失败的诊断和治疗的努力。通过整合来自培养物中 hESC 蜕膜化的全基因组数据集，我们揭示了早幼粒细胞白血病锌指 (PLZF) 转录因子可以被孕酮快速诱导，并且这种诱导对于孕酮依赖性蜕膜化是必不可少的。染色质免疫沉淀和下一代测序 (ChIP-Seq) 鉴定出 PLZF 基因内至少有 10 个黄体酮反应元件，表明 PLZF 可能作为 PGR 信号传导的直接靶点。人类和小鼠子宫内膜中 PLZF 的时空表达谱进一步支持基质 PLZF 作为黄体酮蜕膜信号的介质。为了确定 PLZF 的功能靶标，PLZF ChIP-Seq 和 RNA Pol II RNA-Seq 数据集的整合表明，早期生长反应 1 (EGR1) 转录因子是 PLZF 的靶标，必须降低其表达水平才能实现孕激素依赖性 hESC 蜕膜化。除了对黄体酮驱动 hESC 蜕膜化的分子机制提供重要见解外，我们的研究结果还提供了一个新的概念框架，可能为诊断和/或治疗与子宫功能障碍相关的不良生殖后果开辟新途径。胚胎附着于子宫上皮后，下面的蜕膜化基质对于孕体进一步侵入母体室至关重要。由于子宫内膜蜕膜化是导致成功妊娠的一系列事件的早期所必需的，因此异常蜕膜化不仅会导致植入失败或早期流产，而且可能会引发在随后的妊娠三个月中出现的不良生殖结果。黄体酮引起的全基因组转录变化是蜕膜化的基础。然而，在功能上实现黄体酮驱动的蜕膜化的关键信号尚不完全清楚。通过对基因组规模数据的综合分析以及对原代人子宫内膜基质细胞（hESC）的研究，我们揭示了早幼粒细胞白血病锌指（PLZF）转录因子可以被孕酮快速诱导，并且其诱导对于孕酮依赖性 hESC 蜕膜化至关重要。尽管 PLZF 反过来控制 hESC 中一系列显着的靶基因，但我们证明 PLZF 严格调节早期生长反应 1 (EGR1) 转录因子的表达水平，其扰动会损害孕激素依赖性蜕膜化。总之，我们的研究结果为黄体酮在子宫中的作用提供了新的机制视角，这可能为未来制定更有效的生育解决方案提供新的机会。
Progesterone, via the progesterone receptor (PGR), is essential for endometrial stromal cell decidualization, a cellular transformation event in which stromal fibroblasts differentiate into decidual cells. Uterine decidualization supports embryo implantation and placentation as well as subsequent events, which together ensure a successful pregnancy. Accordingly, impaired decidualization results not only in implantation failure or early fetal miscarriage, but also may lead to potential adverse outcomes in all three pregnancy trimesters. Transcriptional reprogramming on a genome-wide scale underlies progesterone dependent decidualization of the human endometrial stromal cell (hESC). However, identification of the functionally essential signals encoded by these global transcriptional changes remains incomplete. Importantly, this knowledge-gap undercuts future efforts to improve diagnosis and treatment of implantation failure based on a dysfunctional endometrium. By integrating genome-wide datasets derived from decidualization of hESCs in culture, we reveal that the promyelocytic leukemia zinc finger (PLZF) transcription factor is rapidly induced by progesterone and that this induction is indispensable for progesterone-dependent decidualization. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) identified at least ten progesterone response elements within the PLZF gene, indicating that PLZF may act as a direct target of PGR signaling. The spatiotemporal expression profile for PLZF in both the human and mouse endometrium offers further support for stromal PLZF as a mediator of the progesterone decidual signal. To identify functional targets of PLZF, integration of PLZF ChIP-Seq and RNA Pol II RNA-Seq datasets revealed that the early growth response 1 (EGR1) transcription factor is a PLZF target for which its level of expression must be reduced to enable progesterone dependent hESC decidualization. Apart from furnishing essential insights into the molecular mechanisms by which progesterone drives hESC decidualization, our findings provide a new conceptual framework that could lead to new avenues for diagnosis and/or treatment of adverse reproductive outcomes associated with a dysfunctional uterus. Following embryo attachment to the uterine epithelium, the underlying decidualized stroma is critical for further invasion by the conceptus into the maternal compartment. Because endometrial decidualization is required early in the continuum of events that lead to a successful pregnancy, abnormal decidualization can contribute not only to implantation failure or early miscarriage, but may initiate adverse reproductive outcomes that manifest in subsequent pregnancy trimesters. Genome-wide transcriptional changes by progesterone are known to underlie decidualization; however, the pivotal signals that functionally enable progesterone-driven decidualization are not fully known. Using an integrative analysis of genome-scale data along with studies on primary human endometrial stromal cells (hESCs), we reveal that the promyelocytic leukemia zinc finger (PLZF) transcription factor is rapidly induced by progesterone, and its induction is essential for progesterone-dependent hESC decidualization. Although PLZF in turn governs a remarkable array of target genes in the hESC, we demonstrate that PLZF tightly regulates the expression level of the early growth response 1 (EGR1) transcription factor, the perturbation of which compromises progesterone dependent decidualization. Together, our findings provide a new mechanistic perspective on progesterone action in the uterus which may furnish new opportunities for the formulation of more effective fertility solutions in the future.