Progesterone (P), acting via its nuclear receptor (PR), is critical for pregnancy maintenance by suppressing proinflammatory and contraction-associated protein ()/contractile genes in the myometrium. P/PR partially exerts these effects by tethering to NF-κB bound to their promot­ers, thereby decreasing NF-κB transcriptional activity. However, the underlying mechanisms whereby P/PR interaction blocks proinflammatory and gene expression are not fully understood. Herein, we characterized CCR-NOT transcription complex subunit 1 (CNOT1) as a corepressor that also interacts within the same chromatin complex as PR-B. In mouse myome­trium increased expression of genes and at term coincided with a marked decline in expression and binding of to NF-κB-response elements within the and promoters. Increased gene expression was accompanied by a pronounced decrease in enrichment of repressive histone marks and increase in enrichment of active histone marks to this genomic region. These changes in histone modification were associated with changes in expression of corresponding histone modifying enzymes. Myometrial tissues from P-treated 18.5 dpc pregnant mice manifested increased expression at 18.5 dpc, compared to vehicle-treated controls. P treatment of PR-expressing hTERT-HM cells enhanced expression and its recruitment to PR bound NF-κB-response elements within the and promoters. Furthermore, knockdown of significantly increased expression of contractile genes. These novel findings suggest that decreased expression and DNA-binding of the P/PR-regulated transcriptional corepressor near term and associated changes in histone modifications at the and promoters contribute to the induction of myometrial contractility leading to parturition.

中文翻译：

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妊娠子宫肌层中辅阻遏物 CNOT1 的下降近期会损害孕酮受体功能并增加收缩基因表达


黄体酮 (P) 通过其核受体 (PR) 发挥作用，通过抑制子宫肌层中的促炎和收缩相关蛋白 ()/收缩基因，对维持妊娠至关重要。 P/PR 通过束缚与其启动子结合的 NF-κB 来部分发挥这些作用，从而降低 NF-κB 转录活性。然而，P/PR 相互作用阻断促炎和基因表达的潜在机制尚不完全清楚。在此，我们将 CCR-NOT 转录复合物亚基 1 (CNOT1) 定性为辅阻遏物，它也在与 PR-B 相同的染色质复合物内相互作用。在小鼠子宫肌层中，基因表达增加，足月时与启动子内的 NF-κB 反应元件的表达和结合显着下降同时发生。基因表达的增加伴随着该基因组区域抑制性组蛋白标记富集的显着减少和活性组蛋白标记富集的增加。组蛋白修饰的这些变化与相应组蛋白修饰酶的表达变化相关。与媒介物处理的对照相比，P处理的18.5 dpc怀孕小鼠的子宫肌组织在18.5 dpc时表现出表达增加。 P 处理表达 PR 的 hTERT-HM 细胞可增强表达，并招募其至 PR 结合的 NF-κB 反应元件。此外，敲低收缩基因的表达显着增加。这些新发现表明，P/PR 调节的转录辅阻遏物近期表达和 DNA 结合的减少以及 和启动子处组蛋白修饰的相关变化有助于诱导子宫肌层收缩性，从而导致分娩。