HDAC4-AS1/CTCF Transcriptionally Represses HDAC4 Under Stress, Whereas HDAC4 Inhibits Stress-Induced Syncytiotrophoblast Cellular Pyroptosis by Deacetylating NLRP3 and GSDMD

IF 2.7 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Biochemistry and Function Pub Date : 2025-03-18 DOI:10.1002/cbf.70064

Juan Du, Qinghong Ji, Lihua Dong, Lanlan Wang, Gang Xin

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引用次数: 0

Abstract

Our previous study reported that histone deacetylase 4 (HDAC4) expression is significantly downregulated in placental tissues of pre-eclampsia (PE) pregnancies. Cellular pyroptosis is a key event in the pathogenesis of PE that induces the release of factors into the maternal circulation. The aim of this study is to analyze the role and related molecular mechanisms of HDAC4 in PE trophoblast cell pyroptosis. Hypoxia and lipopolysaccharide (LPS)/ATP-treated immortalized human placental villous trophoblast cells HTR-8/SVneo were utilized to mimic the placental trophoblast cell state in PE. Both hypoxia and LPS/ATP treatments induced significant HTR-8/SVneo cell pyroptosis, whereas HDAC4 overexpression inhibited the induced cell pyroptosis. HDAC4 could bind to NLRP3 and GSDMD proteins, and lead to a decrease in acetylated NLRP3 and GSDMD proteins, thereby inhibiting cell pyroptosis. Hypoxia and LPS/ATP treatment significantly upregulated HDAC4-AS1 levels in HRT-8/SVneo cells. HDAC4-AS1 could bind to HDAC4 gene promoter sequences as well as CTCF protein. HDAC4-AS1 overexpression recruited the enrichment of CTCF on HDAC4 promoter sequences and further repressed HDAC4 transcription and expression. Targeting the transcriptional regulatory mechanism of HDAC4-AS1/HDAC4 may be able to ameliorate the clinical symptoms of PE maternal by inhibiting cellular pyroptosis in syncytiotrophoblast cells under stress.

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HDAC4- as1 /CTCF在应激下转录抑制HDAC4，而HDAC4通过去乙酰化NLRP3和GSDMD抑制应激诱导的合胞滋养层细胞焦亡

我们之前的研究报道了组蛋白去乙酰化酶4 （HDAC4）在先兆子痫（PE）妊娠胎盘组织中的表达显著下调。细胞焦亡是PE发病的一个关键事件，它诱导因子释放到母体循环中。本研究旨在分析HDAC4在PE滋养细胞焦亡中的作用及相关分子机制。缺氧和脂多糖(LPS)/ atp处理的人胎盘绒毛滋养细胞HTR-8/SVneo在PE中模拟胎盘滋养细胞状态。低氧和LPS/ATP处理均可诱导HTR-8/SVneo细胞显著焦亡，而HDAC4过表达抑制诱导的细胞焦亡。HDAC4可以结合NLRP3和GSDMD蛋白，导致NLRP3和GSDMD蛋白乙酰化减少，从而抑制细胞焦亡。缺氧和LPS/ATP处理显著上调HRT-8/SVneo细胞中的HDAC4-AS1水平。HDAC4- as1可以结合HDAC4基因启动子序列和CTCF蛋白。HDAC4- as1过表达募集了HDAC4启动子序列上CTCF的富集，进一步抑制了HDAC4的转录和表达。针对HDAC4- as1 /HDAC4的转录调控机制，可能通过抑制应激条件下合胞滋养细胞的细胞热亡，改善PE产妇的临床症状。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Biochemistry and Function 生物-生化与分子生物学

CiteScore

6.20

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Cell Biochemistry and Function publishes original research articles and reviews on the mechanisms whereby molecular and biochemical processes control cellular activity with a particular emphasis on the integration of molecular and cell biology, biochemistry and physiology in the regulation of tissue function in health and disease. The primary remit of the journal is on mammalian biology both in vivo and in vitro but studies of cells in situ are especially encouraged. Observational and pathological studies will be considered providing they include a rational discussion of the possible molecular and biochemical mechanisms behind them and the immediate impact of these observations to our understanding of mammalian biology.