Hypoxia regulates fibrosis-related genes via histone lactylation in the placentas of patients with preeclampsia

Abstract

Background: Histone lactylation, a novel epigenetic modification induced by hypoxia and lactate, plays an important role in regulating gene expression. However, the role of histone lactylation in the pathogenesis of preeclampsia remains unknown.Methods: Placentas from preeclamptic patients and control pregnant women were collected for protein immunoassay to detect the expression level of histone lactylation, and two trophoblast cell lines were used to simulate the effect of histone lactylation on genes.Results: We found that lactate and histone lactylation levels were increased in preeclamptic placentas. In vitro, hypoxia was demonstrated to induce histone lactylation by promoting the production of lactate in human-trophoblastderived cell line (HTR-8/SVneo) and human first-trimester extravillous trophoblast cell line (TEV-1) cells. In addition, 152 genes were found to be upregulated by both hypoxia exposure and sodium L-lactate treatment in HTR-8/SVneo cells. These genes were mainly enriched in the pathways including the response to hypoxia, cell migration and focal adhesion. Among the 152 genes, nine were upregulated in preeclamptic placentas. Most noteworthy, two upregulated fibrosis-related genes, FN1 and SERPINE1, were promoted by hypoxia through histone lactylation mediated by the production of lactate. Conclusions:The present study demonstrated the elevated levels of histone lactylation in preeclamptic placentas and identified fibrosis-related genes that were promoted by histone lactylation induced by hypoxia in trophoblast cells, which provides novel insights into the mechanism of placental dysfunction in preeclampsia.

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

“…qRT-PCR was conducted to confirm this result. Histone lactylation modifications usually regulate the process of glycolysis or inflammation through gene transcription [ 45 ]. ChIP-seq and CUT&Tag assays were employed to ascertain the binding affinity of lactate modification towards relevant genes [ 46 , 47 ].…”

Hypoxia regulates fibrosis-related genes in the placentas of patients with preeclampsia: it credits to histone lactylation?

“…We read with great interest the article by Li et al [1]. In the article, the authors confirmed several fibrosis-related genes induced by hypoxia in trophoblastic cells and identified elevated levels of histone lactylation in preeclampsia placenta, which provides a new view of placental dysfunction in preeclampsia at the level of posttranslational lactylation modification.…”

Post-translational protein lactylation modification in health and diseases: a double-edged sword

“…There is compelling evidence that the upregulation of glycolysis in trophoblast cells, macrophages, and myocardial endothelial cells contributes to the progression of placental, pulmonary, and myocardial fibrosis, respectively [88][89][90]. Reduced blood flow to the uteroplacental unit in preeclampsia leads to a hypoxic condition in the placenta, which in turn promotes excessive lactate production by trophoblast cells and induces histone lactylation to regulate the expression of genes associated with preeclamptic placental fibrosis (FN1 and SERPINE1) [88].…”