PDF(Pubmed)
Abstract：
Progesterone (P4), acting via its nuclear receptor (PR), is critical for pregnancy maintenance by suppressing proinflammatory and contraction-associated protein (CAP)/contractile genes in the myometrium. P4/PR partially exerts these effects by tethering to NF-κB bound to their promot-ers, thereby decreasing NF-κB transcriptional activity. However, the underlying mechanisms whereby P4/PR interaction blocks proinflammatory and CAP 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 myome-trium increased expression of CAP genes Oxtr and Cx43 at term coincided with a marked decline in expression and binding of CNOT1 to NF-κB-response elements within the Oxtr and Cx43 promoters. Increased CAP 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 P4-treated 18.5 dpc pregnant mice manifested increased Cnot1 expression at 18.5 dpc, compared to vehicle-treated controls. P4 treatment of PR-expressing hTERT-HM cells enhanced CNOT1 expression and its recruitment to PR bound NF-κB-response elements within the CX43 and OXTR promoters. Furthermore, knockdown of CNOT1 significantly increased expression of contractile genes. These novel findings suggest that decreased expression and DNA-binding of the P4/PR-regulated transcriptional corepressor CNOT1 near term and associated changes in histone modifications at the OXTR and CX43 promoters contribute to the induction of myometrial contractility leading to parturition.
摘要：
孕酮（P4），通过其核受体（PR）起作用，通过抑制子宫肌层中的促炎和收缩相关蛋白（CAP）/收缩基因对维持妊娠至关重要。P4/PR通过连接到与它们的启动子结合的NF-κB来部分发挥这些作用，从而降低NF-κB转录活性。然而,P4/PR相互作用阻断促炎和CAP基因表达的潜在机制尚不完全清楚.在这里，我们将CCR-NOT转录复合物亚基1（CNOT1）表征为P4诱导的辅抑制因子，其也在与PR-B相同的染色质复合物内相互作用。在小鼠子宫肌层中，CAP基因Oxtr和Cx43的表达增加，同时内源性CNOT1与Oxtr和Cx43启动子内NF-κB反应元件的表达和结合显着下降。CAP基因表达的增加伴随着抑制性组蛋白标记的富集明显减少和活性组蛋白标记对该基因组区域的富集增加。组蛋白修饰的这些变化与相应组蛋白修饰酶表达的变化有关。P4处理的18.5dpc妊娠小鼠的子宫肌层组织在18.5dpc时表现出Cnot1表达增加，与媒介物处理的对照相比。在hTERT-HM细胞中，P4处理增强了CNOT1的表达及其对CX43和OXTR启动子区域内NF-κB反应元件的募集。此外，CNOT1的敲除显着增加了收缩基因的表达。这些新发现表明，近期染色质水平上转录辅抑制因子CNOT1的表达和结合降低以及OXTR和CX43启动子上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。
