MiRNA-Based Regulation of Hemostatic Factors through Hepatic Nuclear Factor-4 Alpha.

Salam Salloum-Asfar,Vicente Vicente,Raúl Teruel-Montoya,Vanessa Roldán,Constantino Martínez,Rocío González-Conejero,Ana B Arroyo,Nuria García-Barberá,Edward E Schmidt

doi:10.1371/journal.pone.0154751

Salam Salloum-Asfar, Vicente Vicente + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0154751

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Journal: PloS one	Publication Date: May 2, 2016
Citations: 20	License type: CC BY 4.0

Affiliation: Centro Regional de Hemodonación, University of Murcia

Abstract

MiRNAs have been reported as CIS-acting elements of several hemostatic factors, however, their mechanism as TRANS-acting elements mediated by a transcription factor is little known and could have important effects. HNF4α has a direct and important role in the regulation of multiple hepatic coagulation genes. Previous in vitro studies have demonstrated that miR-24-3p and miR-34a-5p regulate HNF4A expression. Here we aimed to investigate the molecular mechanisms of miR-24 and miR-34a on coagulation through HNF4A. Transfections with miR-24 and miR-34a in HepG2 cells decreased not only HNF4A but also F10, F12, SERPINC1, PROS1, PROC, and PROZ transcripts levels. Positive and significant correlations were observed between levels of HNF4A and several hemostatic factors (F5, F8, F9, F11, F12, SERPINC1, PROC, and PROS1) in human liver samples (N = 104). However, miR-24 and miR-34a levels of the low (10th) and high (90th) percentiles of those liver samples were inversely correlated with HNF4A and almost all hemostatic factors expression levels. These outcomes suggest that miR-24 and miR-34a might be two indirect elements of regulation of several hemostatic factors. Additionally, variations in miRNA expression profiles could justify, at least in part, changes in HNF4A expression levels and its downstream targets of coagulation.

Highlights

High levels of coagulation factors may disturb the fragile balance of the hemostatic system leading to thrombotic events
To verify whether HNF4A modulates the expression of coagulation factors in human liver, we quantified mRNA levels of HNF4A and 9 genes involved in coagulation (F5, F9, F10, F11, F12, SERPINC1, PROC, PROZ, and PROS1) in 104 human liver samples
The wider expression variability was found for F9 (14–400%) and SERPINC1 (6– 640%) whereas PROC and PROZ had the lower range of variability (Fig 1)

Summary

Introduction

High levels of coagulation factors may disturb the fragile balance of the hemostatic system leading to thrombotic events. Coagulation factors have a substantial interindividual variability in healthy human plasma [1,2] so that the threshold for the individual thrombotic risk will come defined by the joint action of genetic, environmental, and acquired factors [1,3,4,5]. Among the genetic elements that drive the synthesis of coagulation factors a hereditary component has been described for several of them the heritable basis for high or low levels of factors remains unknown [1]. Common regulatory genes coordinate simultaneously the expression of several clotting factors which would allow to categorize individuals in those with high or low levels of coagulation factors [2,4].

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