MEG8 regulates Tissue Factor Pathway Inhibitor 2 (TFPI2) expression in the endothelium

Kremer, Veerle; Bink, Diewertje I.; Stanicek, Laura; Ingen, Eva van; Gimbel, Theresa; Hilderink, Sarah; Günther, Stefan; Nossent, A. Yaël; Boon, Reinier A.

doi:10.1038/s41598-022-04812-z

Cited by 10 publications

(13 citation statements)

References 46 publications

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“…Genes that were predicted to be a target in at least three of the databases were selected. We obtained mRNA expression levels after MEG8 knockdown from our previously published dataset ( ; Kremer et al, 2022 ). When comparing the fold change of predicted miRNA targets to all genes regulated by MEG8, we observed a shift towards increased expression of miRNA targets after loss of MEG8 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…RNA was isolated according to the manufacturer's protocol (Direct-zol RNA miniprep kit, Zymo). Kremer et al, 2022). miRNA-370 and miR-494 targets were predicted using online available tools (miRWalk, miRanda, RNA22 and TargetScan).…”

Section: Cardiac Differentiation Of Hipscmentioning

confidence: 99%

“…Six individual experiments were performed. (E) Gene expression in control and MEG8 GapmeR 1-treated HUVECs was obtained from previously published data (GSE186616;Kremer et al, 2022). miRNA-370 and miR-494 targets were predicted using online available tools (miRWalk, miRanda, RNA22 and TargetScan).…”

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confidence: 99%

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The long non-coding RNA MEG8 induces an endothelial barrier through regulation of microRNA-370 and -494 processing

Kremer

Stanicek

Ingen

et al. 2022

Journal of Cell Science

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The 14q32 locus is an imprinted region in the human genome which contains multiple non-coding RNAs. We investigated the role of Maternally Expressed Gene 8 (MEG8) in endothelial function and the underlying mechanism. A 5-fold increase in MEG8 was observed with increased passage number in Human Umbilical Vein Endothelial Cells, suggesting MEG8 is induced during aging. MEG8 knockdown resulted in a 1.8-fold increase in senescence, suggesting MEG8 might be protective during aging. Endothelial barrier was impaired after MEG8 silencing. MEG8 knockdown resulted in reduced expression of miRNA-370 and -494 but not -127, -487b and -410. Overexpression of miRNA-370/-494 partially rescued MEG8-silencing-induced barrier loss. Mechanistically, MEG8 regulates expression of miRNA-370 and -494 at the mature miRNA level through interaction with RNA binding proteins Cold Inducible RNA Binding Protein (CIRBP) and Hydroxyacyl-CoA Dehydrogenase Trifunctional Multi-enzyme Complex Subunit Beta (HADHB). Precursor and mature miRNA-370/-494 were shown to interact with HADHB and CIRBP respectively. CIRBP/HADHB silencing resulted in downregulation of miRNA-370 and induction of miRNA-494. These results suggest MEG8 interacts with CIRBP and HADHB and contributes to miRNA processing at the post-transcriptional level.

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Section: Resultsmentioning

confidence: 99%

Section: Cardiac Differentiation Of Hipscmentioning

confidence: 99%

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The long non-coding RNA MEG8 induces an endothelial barrier through regulation of microRNA-370 and -494 processing

Kremer

Stanicek

Ingen

et al. 2022

Journal of Cell Science

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“…RNA was isolated using miRNeasy micro kit (Qiagen). Sequencing was performed on the NextSeq500 instrument (Illumina) using v2 chemistry and 1 × 75 bp single-end setup as described previously [ 28 ]. Trimmed and filtered reads were aligned versus the Ensembl human genome version hg38 (GRCh38) using STAR 2.6.1d with the parameter “–outFilterMismatchNoverLmax 0.1” to increase the maximum ratio of mismatches to mapped length to 10%.…”

Section: Methodsmentioning

confidence: 99%

Neuro-oncological Ventral Antigen 2 Regulates Splicing of Vascular Endothelial Growth Factor Receptor 1 and Is Required for Endothelial Function

et al. 2022

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Pre-eclampsia (PE) affects 2–8% of pregnancies and is responsible for significant morbidity and mortality. The maternal clinical syndrome (defined by hypertension, proteinuria, and organ dysfunction) is the result of endothelial dysfunction. The endothelial response to increased levels of soluble FMS-like Tyrosine Kinase 1 (sFLT1) is thought to play a central role. sFLT1 is released from multiple tissues and binds VEGF with high affinity and antagonizes VEGF. Expression of soluble variants of sFLT1 is a result of alternative splicing; however, the mechanism is incompletely understood. We hypothesize that neuro-oncological ventral antigen 2 (NOVA2) contributes to this. NOVA2 was inhibited in human umbilical vein endothelial cells (HUVECs) and multiple cellular functions were assessed. NOVA2 and FLT1 expression in the placenta of PE, pregnancy-induced hypertension, and normotensive controls was measured by RT-qPCR. Loss of NOVA2 in HUVECs resulted in significantly increased levels of sFLT1, but did not affect expression of membrane-bound FLT1. NOVA2 protein was shown to directly interact with FLT1 mRNA. Loss of NOVA2 was also accompanied by impaired endothelial functions such as sprouting. We were able to restore sprouting capacity by exogenous VEGF. We did not observe statistically significant regulation of NOVA2 or sFLT1 in the placenta. However, we observed a negative correlation between sFLT1 and NOVA2 expression levels. In conclusion, NOVA2 was found to regulate FLT1 splicing in the endothelium. Loss of NOVA2 resulted in impaired endothelial function, at least partially dependent on VEGF. In PE patients, we observed a negative correlation between NOVA2 and sFLT1.

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“…RNA sequencing experiments have shown up-regulation of the inhibitor of angiogenesis TFPI2 after MEG8 silencing. From a mechanistical point of view, MEG8 silencing can lead to a decrease in H3K27me3 marks at the TFPI2 promoter [ 20 ]. Table 1 shows summary of in vitro studies about the role of MEG8 in human disorders.…”

Section: Introductionmentioning

confidence: 99%

A review on the role of MEG8 lncRNA in human disorders

et al. 2022

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Maternally expressed 8 (MEG8) is a long non-coding RNA which is expressed in the nucleus. It is highly expressed in adrenal, placenta and brain. Recent studies have shown contribution of MEG8 in different disorders ranging from neoplastic ones to diabetic nephropathy, atherosclerosis, ischemic stroke, trophoblast dysfunction and abortion, Henoch-Schonlein purpura and osteoarthritis. It has an oncogenic role in the development of lung, pancreatic and liver cancer. In the current review, we summarize the role of this lncRNA in mentioned disorders, based on the evidence obtained from in vitro, in vivo and human studies.

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MEG8 regulates Tissue Factor Pathway Inhibitor 2 (TFPI2) expression in the endothelium

Cited by 10 publications

References 46 publications

The long non-coding RNA MEG8 induces an endothelial barrier through regulation of microRNA-370 and -494 processing

The long non-coding RNA MEG8 induces an endothelial barrier through regulation of microRNA-370 and -494 processing

Neuro-oncological Ventral Antigen 2 Regulates Splicing of Vascular Endothelial Growth Factor Receptor 1 and Is Required for Endothelial Function

A review on the role of MEG8 lncRNA in human disorders

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