Identification of transcription factors that regulate placental sFLT1 expression.

IF 3.6 2区 医学 Q2 DEVELOPMENTAL BIOLOGY
Qing Yong, Carin van der Keur, Jacqueline D H Anholts, Hanneke Kapsenberg, Hailiang Mei, Jan A Bruijn, Michael Eikmans, Hans J Baelde
{"title":"Identification of transcription factors that regulate placental sFLT1 expression.","authors":"Qing Yong, Carin van der Keur, Jacqueline D H Anholts, Hanneke Kapsenberg, Hailiang Mei, Jan A Bruijn, Michael Eikmans, Hans J Baelde","doi":"10.1093/molehr/gaaf031","DOIUrl":null,"url":null,"abstract":"<p><p>Increased sFLT1 levels have been associated with preeclampsia, chronic kidney diseases, and kidney transplant rejection. However, lower levels of sFLT1 exhibit beneficial properties in various processes, such as organization of the actin cytoskeleton in podocytes, and immune regulation in healthy pregnancy. Therefore, understanding the transcriptional regulation of sFlt-1 and preserving appropriate expression levels are critical for effective treatment of preeclampsia and other diseases. Cytotrophoblasts (CTBs) were isolated from three first trimester placentas and differentiated into extravillous trophoblasts (EVTs) for six days. RNA was extracted at different time points and used for RNA sequencing. Differentially expressed genes (DEGs) and transcription factors (DETFs) were analyzed. TF enrichment analysis and pathway analysis were performed on DEGs screened from EVTs and CTBs. TF inhibitors were added to primary CTBs directly or during CTB to EVT differentiation to confirm the regulatory effect of TFs on sFLT1 expression. In total, 197 transcription factors were differentially expressed between CTBs and EVTs, among which, 15 DETFs (EPAS1, ETS1, TBX3, CEBPB, FLI1, TEAD4, GATA4, TBX2, LMX1B, ARNT, FOXM1, ERF, PRDM1, TFAP2A and NR2F2) that potentially regulate sFLT1 expression were predicted by ChEA3 and KnockTF software. The mRNA levels of 15 DETFs were validated upon CTBs differentiation into both EVTs and syncytiotrophoblast. The regulatory effects of FOXM1 and CEBPB were confirmed in vitro experiments, and their expression patterns were validated during CTBs differentiation into EVTs and in first trimester placentas. Pathway analysis showed that FLT1 was involved in P13K-Akt, Rap1, MAPK, Ras and HIF-1 signaling pathways, focal adhesion, and cytokine-cytokine receptor interaction. Protein-protein interaction analysis showed FLT4, PDGFB, TGFB1, IL6R, TNFRSF1B, CSF1R, TGFB2 to be interacted with FLT1. The identified transcription factors can serve as therapeutical targets in preeclampsia to keep the sFLT1 levels within appropriate limits.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular human reproduction","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/molehr/gaaf031","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Increased sFLT1 levels have been associated with preeclampsia, chronic kidney diseases, and kidney transplant rejection. However, lower levels of sFLT1 exhibit beneficial properties in various processes, such as organization of the actin cytoskeleton in podocytes, and immune regulation in healthy pregnancy. Therefore, understanding the transcriptional regulation of sFlt-1 and preserving appropriate expression levels are critical for effective treatment of preeclampsia and other diseases. Cytotrophoblasts (CTBs) were isolated from three first trimester placentas and differentiated into extravillous trophoblasts (EVTs) for six days. RNA was extracted at different time points and used for RNA sequencing. Differentially expressed genes (DEGs) and transcription factors (DETFs) were analyzed. TF enrichment analysis and pathway analysis were performed on DEGs screened from EVTs and CTBs. TF inhibitors were added to primary CTBs directly or during CTB to EVT differentiation to confirm the regulatory effect of TFs on sFLT1 expression. In total, 197 transcription factors were differentially expressed between CTBs and EVTs, among which, 15 DETFs (EPAS1, ETS1, TBX3, CEBPB, FLI1, TEAD4, GATA4, TBX2, LMX1B, ARNT, FOXM1, ERF, PRDM1, TFAP2A and NR2F2) that potentially regulate sFLT1 expression were predicted by ChEA3 and KnockTF software. The mRNA levels of 15 DETFs were validated upon CTBs differentiation into both EVTs and syncytiotrophoblast. The regulatory effects of FOXM1 and CEBPB were confirmed in vitro experiments, and their expression patterns were validated during CTBs differentiation into EVTs and in first trimester placentas. Pathway analysis showed that FLT1 was involved in P13K-Akt, Rap1, MAPK, Ras and HIF-1 signaling pathways, focal adhesion, and cytokine-cytokine receptor interaction. Protein-protein interaction analysis showed FLT4, PDGFB, TGFB1, IL6R, TNFRSF1B, CSF1R, TGFB2 to be interacted with FLT1. The identified transcription factors can serve as therapeutical targets in preeclampsia to keep the sFLT1 levels within appropriate limits.

调控胎盘sFLT1表达的转录因子的鉴定。
sFLT1水平升高与子痫前期、慢性肾脏疾病和肾移植排斥反应有关。然而,较低水平的sFLT1在许多过程中表现出有益的特性,例如足细胞中肌动蛋白细胞骨架的组织和健康妊娠中的免疫调节。因此,了解sFlt-1的转录调控并保持适当的表达水平对于有效治疗子痫前期和其他疾病至关重要。从3个妊娠早期胎盘中分离细胞滋养层细胞(CTBs),并将其分化为细胞外滋养层细胞(EVTs) 6天。在不同时间点提取RNA,用于RNA测序。分析差异表达基因(DEGs)和转录因子(detf)。对从evt和CTBs中筛选的deg进行TF富集分析和通路分析。将TF抑制剂直接添加到原代CTBs或在CTB向EVT分化过程中添加,以证实TF对sFLT1表达的调节作用。共有197个转录因子在CTBs和EVTs之间存在差异表达,其中ChEA3和KnockTF软件预测了15个可能调控sFLT1表达的detf (EPAS1、ETS1、TBX3、CEBPB、FLI1、TEAD4、GATA4、TBX2、LMX1B、ARNT、FOXM1、ERF、PRDM1、TFAP2A和NR2F2)。在CTBs分化为evt和合细胞滋养细胞时,验证了15个detf的mRNA水平。体外实验证实了FOXM1和CEBPB的调控作用,并验证了它们在CTBs向evt分化和妊娠早期胎盘中的表达模式。通路分析表明,FLT1参与P13K-Akt、Rap1、MAPK、Ras和HIF-1信号通路、局灶黏附以及细胞因子-细胞因子受体相互作用。蛋白-蛋白相互作用分析显示FLT4、PDGFB、TGFB1、IL6R、TNFRSF1B、CSF1R、TGFB2与FLT1相互作用。鉴定出的转录因子可以作为子痫前期的治疗靶点,使sFLT1水平保持在适当的范围内。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Molecular human reproduction
Molecular human reproduction 生物-发育生物学
CiteScore
8.30
自引率
0.00%
发文量
37
审稿时长
6-12 weeks
期刊介绍: MHR publishes original research reports, commentaries and reviews on topics in the basic science of reproduction, including: reproductive tract physiology and pathology; gonad function and gametogenesis; fertilization; embryo development; implantation; and pregnancy and parturition. Irrespective of the study subject, research papers should have a mechanistic aspect.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信