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Methylation Status of the miR-141-3p Promoter Regulates miR-141-3p Expression, Inflammasome Formation, and the
Dongcai Wu1, Li Shi2, Fangrong Chen1
1Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
Abstract:
MicroRNA-141 (miR-141-3p) is upregulated in preeclampsia. This study investigated the effect of methylation of the miR-141-3p promoter on cell viability, invasion capability, and inflammasomes in vitro. The expression of miR-141-3p and methylation status of the miR-141-3p promoter were examined by RT-qPCR and pyrosequencing in villus tissues of women with spontaneous delivery (VTsd), villus tissues of women with preeclampsia (VTpe), and also in HTR-8/SVneo cells treated with a miR-141-3p inhibitor and 20 μmol/L 5-aza-2'-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor. Cell viability and invasion were evaluated by CCK-8 and transwell assays. In addition, the levels of CXCL12, CXCR4, CXCR2, MMPs, NLRP3, and ASC expression were assessed by western blotting, and IL-1β and IL-18 concentrations were assayed by ELISA. miR-141-3p expression was upregulated, and the levels of miR-141-3p promoter methylation and CXCL12, CXCR4, and CXCR2 expression were decreased in VTpe relative to VTsd. In HTR-8/SVneo cells, hypomethylation caused by 5-Aza treatment increased miR-141-3p expression, while DNA methyltransferase 3 (DNMT3) transfection decreased miR-141-3p expression. miRNA-141-3p induced NLRP3, IL-1β, and IL-18 production, decreased CXCR4, MMP, and MMP2 production, and suppressed cell growth and invasion. Furthermore, we observed that NLRP3 plays an important mediatory role in the effects of miR-141-3p described above. Decreased methylation of the miR-141-3p promoter increases miR-141-3p expression, which in turn increases NLRP3 expression, resulting in higher IL-1β and IL-18 levels and lower levels of MMP2/9 and CXCR4. We conclude that modification of the miR-141-3p promoter might be a curial mediator in preeclampsia.
Insights
Preeclampsia involves increased microRNA-141-3p due to promoter hypomethylation, leading to inflammasome activation and reduced invasion. This suggests miR-141-3p promoter modification is a key factor in preeclampsia pathogenesis.
Area of Science:
- Reproductive biology
- Molecular biology
- Genetics
Background:
- Preeclampsia is a pregnancy complication characterized by hypertension and organ damage.
- MicroRNA-141-3p (miR-141-3p) is implicated in preeclampsia pathogenesis.
- The role of miR-141-3p promoter methylation in preeclampsia remains unclear.
Purpose of the Study:
- To investigate the impact of miR-141-3p promoter methylation on cellular functions in preeclampsia.
- To elucidate the relationship between miR-141-3p expression, methylation, and inflammasome activation.
Main Methods:
- Analysis of miR-141-3p expression and promoter methylation in preeclampsia villus tissues.
- In vitro studies using HTR-8/SVneo cells treated with methylation inhibitors/activators.
- Assessment of cell viability, invasion, and inflammasome components (NLRP3, ASC, IL-1β, IL-18).
Main Results:
- Preeclampsia tissues showed decreased miR-141-3p promoter methylation and increased miR-141-3p expression.
- Hypomethylation enhanced miR-141-3p expression, suppressing cell invasion and promoting inflammasome activation.
- miR-141-3p upregulation increased NLRP3, IL-1β, and IL-18, while decreasing MMPs and CXCR4.
Conclusions:
- Decreased miR-141-3p promoter methylation is associated with preeclampsia.
- Upregulated miR-141-3p, driven by hypomethylation, contributes to preeclampsia pathophysiology via inflammasome activation.
- Modulation of the miR-141-3p promoter is a potential therapeutic target for preeclampsia.
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