H3K4me3-Mediated Upregulation of LncRNA-HEIPP in Preeclampsia Placenta Affects Invasion of Trophoblast Cells

Abstract

Preeclampsia (PE) is a pregnancy-related disease defined as onset of hypertension and proteinuria after the 20th week of pregnancy, which causes most maternal and perinatal morbidity and mortality. Although placental dysfunction is considered as the main cause of PE, the exact pathogenesis of PE is not yet fully understood. Long non-coding RNAs (lncRNAs) are implicated in a broad range of physiological and pathological processes, including the occurrence of PE. In this study, we investigated the expression and functions of HIF-1α pathway–related lncRNA-HEIPP (high expression in PE placenta) in the pathogenesis of PE. The expression of lncRNA-HEIPP in the placenta from women who underwent PE was screened by lncRNA microarray and then verified using real-time polymerase chain reaction. Then, the methylation profile of the lncRNA-HEIPP promoter and the enrichment of H3K4me3 binding were assessed by bisulfite pyrosequencing and chromatin immunoprecipitation (ChIP)–quantitative polymerase chain reaction (qPCR) assay, respectively. It was found that the level of lncRNA-HEIPP in the PE placenta was significantly higher than that in normal placenta and was increased in HTR-8/SVneo human trophoblast cells upon hypoxia treatment. Moreover, we reported that H3K4me3 manifested significantly higher promoter occupancy on lncRNA-HEIPP promoter in HTR-8/SVneo cells upon hypoxia treatment and found that the downregulation of lncRNA-HEIPP promoted trophoblast invasion. Our findings suggested that the hypoxia-induced expression of lncRNA-HEIPP mediated by H3K4me3 modification in trophoblast may contribute to the pathogenesis of PE.

Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

“…However, many genes with deregulated expression were not associated with DNA methylation raising the possibility of altered chromatin signatures leading to abnormal gene expression in this placental disorder (Leavey et al, 2018). Indeed, upregulated expression of LncRNA by increased H3K4me3 has been observed in preeclampsia placentas (Sun et al, 2020), and the levels of H3K4me3 as detected by immunocytochemistry are decreased (Meister et al, 2021). Until now the connection between sperm chromatin and placenta function has been unexplored.…”

Hypoxia induced‐disruption of lncRNA TUG1/PRC2 interaction impairs human trophoblast invasion through epigenetically activating Nodal/ALK7 signalling

“…Successful placental and foetal development during the progression of pregnancy require adequate invasion of extravillous trophoblast cells into the uterine, and impaired trophoblastic invasion and spiral artery remodelling are widely considered as hallmarks of PE 3,4 . According to the literature, reduced trophoblastic invasion and spiral artery remodelling may be due to abnormal trophoblast differentiation, migration, angiogenesis and apoptosis, which may cause reduced uteroplacental perfusion and trigger hypoxia and inflammatory responses in the placenta, and may finally result in the occurrence of PE 5–10 . Besides, a variety of other potential molecular mechanisms have been suggested, including oxidative stress, endoplasmic stress, altered NK cell signalling and others 11 .…”

“…In prostate cancer cells, EZH2 expression can be targeted by miR‐101 upon hypoxia‐inducible factor 1α/β (HIF‐1α/β) induction 29 . HIF is a transcription factor protected from degradation in various cells under hypoxic conditions and plays an essential role in modulating responses to hypoxia by controlling the expression of multiple genes 10,30 . HIF‐1α is stabilized when the concentrations of oxygen are below the specific critical oxygen threshold thus accumulating in the hypoxic cell, and HIF‐1β is constitutively present in the cell nucleus 31 .…”

“…HIF‐1α is stabilized when the concentrations of oxygen are below the specific critical oxygen threshold thus accumulating in the hypoxic cell, and HIF‐1β is constitutively present in the cell nucleus 31 . Numerous studies have illustrated that hypoxia‐reperfusion‐type injuries to the placenta in PE is due to inadequate placental perfusion as a result of insufficient trophoblast invasion and spiral artery remodelling; and HIF‐1α and its targets genes, including vascular endothelial growth factor (VEGF), VEGF‐receptor 1, placental growth factor, platelet‐derived growth factor and matrix metalloproteinases (MMPs), are altered in preeclamptic placenta and thus may be playing a pivotal role during the development of PE 10,32 . Nonetheless, it is unknown how the key component of PRC2, EZH2 to be specific, would be affected in trophoblast under hypoxic conditions and in the pathogenesis of PE.…”

Expression and clinical significance of lncRNA NORAD in patients with gestational hypertension

“…Song et al have confirmed that some lncRNAs may participate in the pathogenesis of preeclampsia through methylation and signaling pathways [14]. Sun et al also studied the effect of the lncRNA-HEIPP expression on the pathogenesis of preeclampsia [15]. These findings suggested that lncRNA may play a role in hypertensive disorders in pregnancy.…”