HDAC4 regulates the proliferation, migration, and invasion of trophoblasts in pre-eclampsia through the miR-134-5p/FOXM1 axis

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Reproduction and Development Pub Date : 2023-09-28 DOI:10.1002/mrd.23706
Yanli Xu, Xiaodi Kang, Hongli Jiang, Huafang Liu, Wenjing Wang
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Abstract

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-2ʹdeoxyuridine, 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.

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HDAC4通过miR-134-5p/FOXM1轴调节子痫前期滋养层细胞的增殖、迁移和侵袭。
表观遗传学,包括组蛋白修饰和非编码RNA,影响子痫前期(PE)的异常胎盘功能。本研究旨在探讨组蛋白脱乙酰酶4(HDAC4)在滋养层细胞侵袭和迁移中的作用。研究了HDAC4、微小RNA(miR)-134-5p和叉头盒蛋白M1(FOXM1)在PE患者和健康对照胎盘中的表达水平及其相关性。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和划痕试验评估滋养层细胞的增殖、侵袭和迁移。HDAC4和赖氨酸9乙酰化组蛋白H3(H3K9Ac)在miR-134-5p启动子上的富集通过染色质免疫沉淀进行定量。通过双荧光素酶测定分析miR-134-5p与FOXM1的结合。在PE胎盘中HDAC4和FOXM1被下调,而miR-134-5p被上调。HDAC4下调损害滋养层细胞的增殖、侵袭和迁移,而HDAC4过表达则起相反的作用。在机制上,HDAC4通过擦除H3K9Ac来脱乙酰H3K9Ac以抑制miR-134-5p的表达,减少miR-134-5p与FOXM1的结合,然后促进FOXM1转录。miR-134-5p过表达或FOXM1下调消除了HDAC过表达在滋养层侵袭和迁移中的促进作用。我们的研究揭示了滋养层细胞增殖、侵袭和迁移的新机制,并提出HDAC4可能是治疗PE的一个有前途的靶点。
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来源期刊
CiteScore
5.20
自引率
0.00%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Reproduction and Development takes an integrated, systems-biology approach to understand the dynamic continuum of cellular, reproductive, and developmental processes. This journal fosters dialogue among diverse disciplines through primary research communications and educational forums, with the philosophy that fundamental findings within the life sciences result from a convergence of disciplines. Increasingly, readers of the Journal need to be informed of diverse, yet integrated, topics impinging on their areas of interest. This requires an expansion in thinking towards non-traditional, interdisciplinary experimental design and data analysis.
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