Rs4759314 polymorphism located in HOTAIR is associated with the risk of congenital heart disease by alternating downstream signaling via reducing its expression

Abstract

Our study was aimed to investigate the mechanism of rs4759314 located in HOTAIR involved in congenital heart disease. Luciferase assay was performed to evaluate whether rs4759314 affected the transcription efficiency of HOTAIR promoter, and confirm miR-545 target gene. Real-time PCR, Western-blot and IHC were carried out to investigate the relationship among HOTAIR, EGFR, p-ERK, P-P38 MAPK. MTT assay and flow cytometry analysis were performed to detect the effect of HOTAIR on cell viability and apoptosis. The presence of G allele of the polymorphism located in HOTAIR promoted transcription activity of HOTAIR promoter. Furthermore, HOTAIR inhibited miR-545 expression. EGFR was identified as a virtual target gene of miR-545 using bioinformatics analysis, and miR-545 apparently decreased luciferase activity of wild-type EGFR 3'UTR, while miR-545 had no effect on luciferase activity of mutant EGFR 3'UTR. HOTAIR and EGFR were lowly expressed, while miR-545 was highly expressed in VSD group. Higher levels of HOTAIR and ECFR, while a lower level of miR-545 were observed in AG than AA groups. Regulatory relationships between HOTAIR and miR-545, as well as EGFR and miR-545 were found to be negatively correlated, with the negative correlation coefficient being -0.49 and -0.46, respectively. HOTAIR evidently increased EGFR p-ERK and P-P38 MAPK expression levels, moreover HOTAIR substantially promoted cell viability, and inhibited cell apoptosis. In this study, we suggested the possible relation between the rs4759314 polymorphism and the risk of congenital heart disease, and explored the deregulation of HOTAIR/miR-545/EGFR/MAPK signaling pathway in the pathogenesis of congenital heart disease.

Rs145204276 and rs4759314 affect the prognosis of prostate cancer by modulating the GAS5/miR-1284/HMGB1 and HOTAIR/miR-22/HMGB1 signalling pathways

“…In addition, GAS5 and HOTAIR play a role as competing endogenous RNAs against miR-1284 and miR-22, respectively [21,23]. Furthermore, the rs145204276 and rs4759314 polymorphisms located in the promoters of GAS5 and HOTAIR, respectively, can affect the transcription efficiency of these promoters [24,25]. Therefore, the two polymorphisms may affect the prognosis of PC via modulating the GAS5/miR-1284/HMGB1 and HOTAIR/miR-22/HMGB1 signalling pathways.…”

Peer Review #1 of "The biomarkers of key miRNAs and target genes associated with acute myocardial infarction (v0.1)"

“…Additionally, the remaining 7 miRNAs have been shown to regulate cardiac performance. miR-545, the negatively correlated target of HOTAIR, promotes cell apoptosis through the HOTAIR/miR-545/EGFR/MAPK axis (Li et al 2018). miR-101 has been shown to mitigate the deterioration of cardiac function in post-MI rats (Pan et al 2012), and it can protect cardiac fibroblasts from hypoxia-induced apoptosis by restraining the TGF-β signalling pathway, as shown by Zhao et al (Zhao et al 2015).…”

CHDGKB: a knowledgebase for systematic understanding of genetic variations associated with non-syndromic congenital heart disease

“…The top eight significant enriched terms of KEGG pathways along with number of genes for isolated and non-isolated CHD can be seen in Figure 8 . Series of MAPK signaling pathways ( 23 ), signaling pathways regulating pluripotency of stem cells ( 24 ) and Rap1 signaling pathway ( 25 ) are essential for occurrence of both isolated and non-isolated CHD.…”