甲基转移酶样14 (METTL14)介导的n6 -甲基腺苷(m6A)修饰叉头盒蛋白1 (FOXP1)通过跨膜BAX抑制剂Motif-Containing 6 (TMBIM6)调控滋养细胞炎症和功能

IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yanhua Liu, Yingru Liu, Xiaoying Zhang, Xiaoxiong Zhu, Yaping Liu
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引用次数: 0

摘要

子痫前期(PE)是一种以滋养细胞功能受损为特征的严重妊娠并发症。虽然甲基转移酶样14 (METTL14)与PE发病机制和滋养细胞功能障碍有关,但其确切的分子机制尚不清楚。采用实时定量聚合酶链反应(qRT-PCR)检测mRNA表达。免疫印迹法评价蛋白表达。总n6 -甲基腺苷(m6A) RNA甲基化使用检测试剂盒进行分析。分别用试管形成法、transwell法和集落形成法评估细胞管形成、侵袭和集落形成。采用酶联免疫吸附法(ELISA)测定白细胞介素-8 (IL-8)、白细胞介素-1β (IL-1β)和白细胞介素-6水平。采用甲基化RNA免疫沉淀法(MeRIP)和mRNA稳定法检测METTL14对叉头盒蛋白1 (FOXP1)的影响。FOXP1/跨膜BAX抑制剂motif-containing 6 (TMBIM6)的关系通过染色质免疫沉淀(ChIP)和荧光素酶测定得到验证。PE患者胎盘样品中总m6A甲基化水平和METTL14表达显著升高。METTL14的过表达降低了人HTR-8/SVneo滋养细胞的细胞集落形成、侵袭和成管能力,促进了促炎细胞因子的产生。METTL14通过m6A依赖机制表观遗传地降低FOXP1的表达。FOXP1的重新表达对mettl14驱动的HTR-8/SVneo细胞功能障碍和炎症具有抵消作用。FOXP1促进TMBIM6的转录,METTL14通过FOXP1降低TMBIM6的表达。FOXP1通过TMBIM6调节HTR-8/SVneo细胞表型和炎症。我们的研究结果确定了一种新的表观遗传机制,即METTL14/FOXP1/TMBIM6轴,具有影响滋养细胞功能和炎症的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine (m6A) Modification of Forkhead Box Protein 1 (FOXP1) Regulates Trophoblast Inflammation and Function via Transmembrane BAX Inhibitor Motif-Containing 6 (TMBIM6)

Methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine (m6A) Modification of Forkhead Box Protein 1 (FOXP1) Regulates Trophoblast Inflammation and Function via Transmembrane BAX Inhibitor Motif-Containing 6 (TMBIM6)

Pre-eclampsia (PE) represents a serious pregnancy complication characterized by impaired trophoblast function. Although methyltransferase-like 14 (METTL14) has been implicated in PE pathogenesis and trophoblast dysfunction, its precise molecular mechanisms remain unclear. mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Immunoblot analysis was used for protein expression evaluation. Total N6-methyladenosine (m6A) RNA methylation was analyzed using an assay kit. Cell tube formation, invasion and colony formation were assessed by tube formation, transwell and colony formation assays, respectively. Interleukin-8 (IL-8), IL-1beta (IL-1β), and IL-6 levels were quantified by enzyme-linked immunosorbent assay (ELISA). The influence of METTL14 in forkhead box protein 1 (FOXP1) was tested by methylated RNA immunoprecipitation (MeRIP) and mRNA stabilization assays. The FOXP1/transmembrane BAX inhibitor motif-containing 6 (TMBIM6) relationship was validated by chromatin immunoprecipitation (ChIP) and luciferase assays. Total m6A methylation levels and METTL14 expression were significantly increased in placental samples of PE patients. Overexpression of METTL14 diminished cell colony formation, invasion, and tube formation abilities of human HTR-8/SVneo trophoblast cells and promoted their pro-inflammatory cytokine production. METTL14 epigenetically reduced FOXP1 expression via an m6A dependent mechanism. Re-expression of FOXP1 exerted a counteracting impact on METTL14-driven dysfunction and inflammation of HTR-8/SVneo cells. FOXP1 promoted TMBIM6 transcription, and METTL14 reduced TMBIM6 expression by FOXP1. FOXP1 regulated HTR-8/SVneo cell phenotypes and inflammation by TMBIM6. Our findings identify a new epigenetic mechanism, the METTL14/FOXP1/TMBIM6 axis, with the ability to affect trophoblast function and inflammation.

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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
期刊介绍: The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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