Department of Obstetrics and Gynecology, Beijing Ditan Hospital Affiliated Capital Medical University, Beijing, China.
Mol Reprod Dev. 2023 Dec;90(12):849-860. doi: 10.1002/mrd.23706. Epub 2023 Sep 28.
Epigenetics, including histone modifications and noncoding RNAs, affects abnormal placental function in pre-eclampsia (PE). This study was conducted to explore the role of histone deacetylase 4 (HDAC4) in trophoblast invasion and migration. The expression levels of HDAC4, microRNA (miR)-134-5p, and forkhead box protein M1 (FOXM1) in placentas from PE patients and healthy controls and their correlations were examined. HTR8/SVneo cells were cultured and underwent gene intervention. Then, trophoblast proliferation, invasion, and migration were evaluated by 5-ethynyl-2'deoxyuridine, Transwell, and scratch assays. The enrichments of HDAC4 and acetylated histone H3 at lysine 9 (H3K9Ac) on the miR-134-5p promoter were quantified by chromatin immunoprecipitation. The binding of miR-134-5p to FOXM1 was analyzed by dual-luciferase assay. HDAC4 and FOXM1 were downregulated while miR-134-5p was upregulated in PE placentas. HDAC4 downregulation impaired trophoblast proliferation, invasion, and migration while HDAC4 overexpression played the opposite role. Mechanically, HDAC4 deacetylated H3K9Ac to repress miR-134-5p expression by erasing H3K9Ac, reduced the binding of miR-134-5p to FOXM1, and then promoted FOXM1 transcription. miR-134-5p overexpression or FOXM1 downregulation abrogated the promotive role of HDAC overexpression in trophoblast invasion and migration. Our study unraveled a novel mechanism of trophoblast proliferation, invasion, and migration and proposed that HDAC4 may be a promising target for the treatment of PE.
表观遗传学，包括组蛋白修饰和非编码 RNA，会影响子痫前期（PE）中胎盘的异常功能。本研究旨在探索组蛋白去乙酰化酶 4（HDAC4）在滋养细胞侵袭和迁移中的作用。检测了 PE 患者和健康对照者胎盘组织中 HDAC4、微小 RNA（miR）-134-5p 和叉头框蛋白 M1（FOXM1）的表达水平，并分析了它们之间的相关性。培养 HTR8/SVneo 细胞并进行基因干预。然后通过 5-乙炔基-2'-脱氧尿苷、Transwell 和划痕实验评估滋养细胞的增殖、侵袭和迁移。通过染色质免疫沉淀定量分析 miR-134-5p 启动子上 HDAC4 和组蛋白 H3 赖氨酸 9 乙酰化（H3K9Ac）的富集。通过双荧光素酶报告基因实验分析 miR-134-5p 与 FOXM1 的结合。PE 胎盘组织中 HDAC4 和 FOXM1 下调，miR-134-5p 上调。HDAC4 下调会损害滋养细胞的增殖、侵袭和迁移，而过表达 HDAC4 则起到相反的作用。机制上，HDAC4 通过消除 H3K9Ac 使 H3K9Ac 去乙酰化，从而抑制 miR-134-5p 的表达，减少 miR-134-5p 与 FOXM1 的结合，进而促进 FOXM1 转录。miR-134-5p 过表达或 FOXM1 下调会消除 HDAC 过表达对滋养细胞侵袭和迁移的促进作用。本研究揭示了滋养细胞增殖、侵袭和迁移的新机制，并提出 HDAC4 可能是治疗 PE 的有前途的靶点。
