C/EBPd drives key endocrine signals in human fetal membranes at parturition [ChIP-seq]

Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of the common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), the key enzymes in their production, may hold the key to the treatment of pre- and post-term labor. Here, we have found that the CCAAT enhancer binding protein d (C/EBPd)?is such a transcription factor which underlies the feed-forward induction of COX-2 and 11ß-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPd?in amnion increases along with COX-2 and 11ß-HSD1 at term and further increases at parturition. Knockout of C/EBPd in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPd?may serve as a novel pharmaceutical target in the amnion for treatment of pre- and post-term labor. Overall design: Examination of different C/EBPd binding site upon cortisol stimulation in human amnion cells with ChIP-seq.

羊膜源性前列腺素E2（PGE2）与皮质醇是分娩启动的关键调控因子。鉴定可同时驱动环氧合酶2（COX-2）与11β-羟类固醇脱氢酶1（11β-HSD1）——二者分别为PGE2与皮质醇合成的关键酶——表达的共同转录因子，或可为早产与过期产的治疗提供新方向。本研究发现，CCAAT增强子结合蛋白δ（C/EBPδ）正是此类转录因子：它可介导人羊膜成纤维细胞中，PGE2与皮质醇对COX-2及11β-HSD1表达的前馈诱导，从而确保羊膜组织中二者的合成以启动分娩。进一步研究显示，羊膜组织中C/EBPδ的表达丰度在妊娠足月时与COX-2、11β-HSD1同步升高，并在分娩时进一步上调。小鼠体内C/EBPδ基因敲除可延迟分娩启动，进一步验证了这一观点。综上，C/EBPδ可作为羊膜组织中治疗早产与过期产的新型药物靶点。实验整体设计：采用染色质免疫共沉淀测序（ChIP-seq）检测人羊膜细胞在皮质醇刺激下的不同C/EBPδ结合位点。