The histone demethylase KDM5C represses trophoblast proliferation and invasion in woman with recurrent miscarriage [ChIP-seq]

KDM5C is a H3K4- specific demethylase, which has multiple biological roles in development and disease. However, the role of KDM5C in trophoblasts at the maternal-fetal interface remains unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from patient with recurrent miscarriage (RM). Trophoblasts proliferation and invasion was inhibited by KDM5C overexpression and was enhanced by KDM5C knockdown. Interestingly, KDM5C knockdown promoted trophoblast invasion in villous explant culture system. RNA-seq and ChIP-seq analyses revealed that KDM5C exerts anti-proliferation and anti-invasion effect by directly modulating H3K4 methylation level to repress the expression of a number of key regulatory genes. We show that two of these genes, TGFβ2, RAGE, are essential for the proliferation and invasion of trophoblasts. Taken together, our results show that the KDM5C is regulator of trophoblast function during early pregnancy and indicated that KDM5C may be involved in the pathogenesis of RM. To characterize genome-wide H3K4me3 chromatin-state of HTR-8/SVneo cells. Examination of H3K4me3 in HTR-8/SVneo cells transduced with control or KDM5C-expression vector

KDM5C是一种H3K4特异性去甲基化酶（H3K4-specific demethylase），在发育与疾病进程中发挥多重生物学功能。然而，KDM5C在母胎界面滋养层细胞中的作用仍未明确。本研究发现，复发性流产（recurrent miscarriage, RM）患者的胎盘滋养层细胞中KDM5C表达上调。KDM5C过表达会抑制滋养层细胞的增殖与侵袭能力，而KDM5C敲低则可增强其增殖与侵袭能力。值得注意的是，在绒毛外植体培养体系中，KDM5C敲低可促进滋养层细胞的侵袭能力。通过RNA测序（RNA-seq）与染色质免疫沉淀测序（ChIP-seq）分析，本研究揭示KDM5C通过直接调控H3K4甲基化水平，抑制多个关键调控基因的表达，从而发挥抗增殖与抗侵袭的作用。本研究证实，其中两个基因——转化生长因子β2（TGFβ2）与晚期糖基化终末产物受体（RAGE）——对滋养层细胞的增殖与侵袭至关重要。综上，本研究结果表明KDM5C是早期妊娠过程中滋养层细胞功能的调控因子，并提示KDM5C可能参与复发性流产的发病机制。为表征HTR-8/SVneo细胞全基因组范围的H3K4me3染色质状态，本研究对转染对照载体或KDM5C过表达载体的HTR-8/SVneo细胞开展了H3K4me3检测分析。