Transcriptome Profiling Reveals the Endogenous Sponging Role of LINC00659 and UST-AS1 in High-Altitude Induced Thrombosis

Abstract

Background: The pathophysiology of Deep vein thrombosis (DVT) is considered as multifactorial, where thrombus formation is interplay of genetic and acquired risk factors. A little is known about the expression profile and roles of lncRNAs in human subjects developing DVT at high altitude. Methods: Using RNAseq, we compared peripheral blood mRNA and lncRNA expression profile in human High Altitude deep Vein Thrombosis (HA-DVT) patients with high altitude control subjects. We used DESeq to identify differentially expressed (DE) genes. We annotated the long noncoding RNAs using NONCODE 3.0 database. In silico putative lncRNA-miRNA association study unravels the endogenous miRNA sponge associated with our candidate lncRNAs. These findings were validated by siRNA knockdown assay of the candidate lncRNAs conducted in primary endothelial cells. Results: We identified 1524 DE mRNA and 973 DE lncRNAs. Co-expressed protein-coding genes analysis resulted in a list of 722 coexpressed protein-coding genes with a Pearson correlation coefficients >0.7. The functional annotation of co-expressed genes and putative proteins revealed their involvement in the hypoxia, immune response and coagulation cascade. Through its miRNA response elements (MREs) to compete for miR-143 and miR-15, lncRNA-LINC00659 and UXT-AS1 regulates the expression of prothrombotic genes. Furthermore, in vitro RNA interference (siRNA) simultaneously suppressed lncRNAs and target gene mRNA level. Conclusions: This transcriptome profile describes novel potential mechanisms of interaction between lncRNAs, the coding genes, miRNAs and regulatory transcription factors that define the thrombotic signature and may be used in establishing lncRNAs as biomarker in HA-DVT.

The Impact of Temporary Stay at High Altitude on the Circulatory System

“…A biomarker that may be used in future for testing of patients who develop high altitude deep vein thrombosis is lncRNA (long non-coding RNAs), as suggested in novel studies by Jha et al [84]. There is no consensus on the relationship between the frequency of stroke and being at high altitude.…”

By modulating miR‐525‐5p/Bax axis, LINC00659 promotes vascular endothelial cell apoptosis

“…LINC00659 was found to be involved in varieties of diseases, including cancer and venous thrombosis 22–24 . These studies imply that the mechanism of LINC00659 involved in disease is related to the miRNA regulatory network 36 .…”

“…LINC00659, a novel lncRNA involved in tumorigenesis, acts as the oncogene to regulate cell growth in colorectal cancer 23,24 . Recent findings have shown that LINC00659 is significantly overexpressed in patients with DVT 22 . However, the potential function of LINC00659 in DVT is unclear.…”

“…MicroRNAs (miRNAs) are the class of evolutionarily conserved noncoding RNAs with the function of regulating gene expression at the translational level 25,26 . MiRNAs were reported to play important roles in development of DVT, and lncRNAs were involved in regulation of DVT as competitive RNAs (ceRNAs) for miRNAs 13,22,27–29 . Study has shown that GUSBP5‐AS regulates angiogenesis and proliferation of EPCs through miR‐223‐3p, and alleviates development of DVT 30 .…”

Long Noncoding RNAs—Biomarkers for High-Altitude-Induced Thrombosis and Beyond?

“…In this issue of Thrombosis and Haemostasis, Jha and colleagues describe a link between particular noncoding RNAs and high-altitude induced DVT. 4 High-altitude exposure is known to activate the coagulation system. 5 By analyzing the expression profile of lncRNAs, Jha and colleagues show here that higher levels of the lncRNAs LINC00659 and UXT-AS1 are present in peripheral blood from patients suffering from high-altitude-induced DVT as compared with levels seen in high-altitude control subjects without DVT.…”