Lnc-HZ06 down-regulates HIF1α protein levels in CoCl2-exposed hypoxic trophoblast cells and villous tissues of miscarriage patients

IF 8.2 1区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Science of the Total Environment Pub Date : 2025-04-21 DOI:10.1016/j.scitotenv.2025.179477

Peng Tian , Jingsong Zhao , Jiarong Guo , Geng Guo , Liqin Zeng , Qiong Lei , Weina Chen , Xia Fu , Xianjie Shi , Zhongyan Xu , Depeng Zhao , Zhihong Zhang , Huidong Zhang

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Abstract

Hypoxia plays significant roles in various biological processes. In recent study, we have found that a novel lnc-HZ06 promotes the SUMOylation of HIF1α in hypoxic human trophoblast cells. Since environmental cobalt (Co) exposure causes trophoblast cell hypoxia, whether and how lnc-HZ06 might regulate the protein levels of HIF1α, an important biomarker of hypoxia, in CoCl₂-exposed hypoxic trophoblast cells is still unexplored. In this study, we find that lnc-HZ06 is highly expressed in CoCl₂-exposed trophoblast cells; and lnc-HZ06 further down-regulates HIF1α protein levels. In details, (1) lnc-HZ06 up-regulates METTL14 (methyltransferase-like 14) and increases m⁶A (N6-methyladenosine) RNA modification levels on VHL (a ubiquitin E3 ligase of HIF1α) mRNA, and thus enhances its mRNA stability and up-regulates VHL mRNA levels. (2) VHL interacts with the SUMOylated HIF1α and promotes the ubiquitination of HIF1α, and finally lnc-HZ06 promotes the ubiquitination degradation of HIF1α protein in CoCl₂-exposed hypoxic trophoblast cells. Therefore, lnc-HZ06 promotes VHL-mediated HIF1α protein degradation and down-regulates HIF1α protein levels. The cellular mechanisms in hypoxic trophoblast cells were partially consistent to those in villous tissues of patients with unexplained miscarriage (UM), expect for no significantly different Co content in UM and healthy control (HC) villous tissues. Collectively, this study discovers novel regulatory roles of lnc-HZ06 and m⁶A modification and post-translational modification (SUMO/Ubiquitin) in HIF1α protein levels in hypoxic human trophoblast cells.

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Lnc-HZ06下调cocl2暴露的流产患者缺氧滋养细胞和绒毛组织中HIF1α蛋白水平

缺氧在多种生物过程中起着重要作用。在最近的研究中，我们发现一种新的lnc-HZ06在缺氧的人滋养细胞中促进HIF1α的sumo化。由于环境钴（Co）暴露导致滋养细胞缺氧，lnc-HZ06是否以及如何调节cocl2暴露的缺氧滋养细胞中重要的缺氧生物标志物HIF1α的蛋白水平仍未研究。在本研究中，我们发现lnc-HZ06在cocl2暴露的滋养细胞中高表达；lnc-HZ06进一步下调HIF1α蛋白水平。(1) lnc-HZ06上调METTL14 (methyltransferase-like 14)，增加m6A （n6 -甲基腺苷）RNA修饰VHL （HIF1α的一种泛素E3连接酶）mRNA的水平，从而增强其mRNA稳定性，上调VHL mRNA水平。(2) VHL与SUMOylated的HIF1α相互作用，促进HIF1α的泛素化，最终lnc-HZ06促进cocl2暴露的缺氧滋养细胞中HIF1α蛋白的泛素化降解。因此，lnc-HZ06促进vhl介导的HIF1α蛋白降解，下调HIF1α蛋白水平。缺氧滋养细胞的细胞机制与不明原因流产（UM）患者绒毛组织中的细胞机制部分一致，但在UM和健康对照（HC）绒毛组织中Co含量没有显著差异。总之，本研究发现了lnc-HZ06和m6A修饰以及翻译后修饰（SUMO/Ubiquitin）在缺氧人滋养细胞中对HIF1α蛋白水平的新调控作用。

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来源期刊

Science of the Total Environment 环境科学-环境科学

CiteScore

17.60

自引率

10.20%

发文量

8726

审稿时长

2.4 months

期刊介绍： The Science of the Total Environment is an international journal dedicated to scientific research on the environment and its interaction with humanity. It covers a wide range of disciplines and seeks to publish innovative, hypothesis-driven, and impactful research that explores the entire environment, including the atmosphere, lithosphere, hydrosphere, biosphere, and anthroposphere. The journal's updated Aims & Scope emphasizes the importance of interdisciplinary environmental research with broad impact. Priority is given to studies that advance fundamental understanding and explore the interconnectedness of multiple environmental spheres. Field studies are preferred, while laboratory experiments must demonstrate significant methodological advancements or mechanistic insights with direct relevance to the environment.