Kurzfassung

Complex molecular networks control the regulation of biological functions. miRNAs confer robustness to the control of these networks through the post-transcriptional fine-tuning of gene expression. Multiple miRNAs can cooperatively regulate a single mRNA to gain regulatory specificity, with the targeting of particular hub genes enabling the regulation of entire pathophysiological pathways. Additionally individual miRNAs can target a large number of mRNAs allowing the broad regulation of...Complex molecular networks control the regulation of biological functions. miRNAs confer robustness to the control of these networks through the post-transcriptional fine-tuning of gene expression. Multiple miRNAs can cooperatively regulate a single mRNA to gain regulatory specificity, with the targeting of particular hub genes enabling the regulation of entire pathophysiological pathways. Additionally individual miRNAs can target a large number of mRNAs allowing the broad regulation of molecular networks constituting biological meaningful pathways. Interestingly, despite the ubiquitous involvement of miRNAs in almost all biological processes, their role in the hemostatic control has remained poorly defined.
Here, we set out to comprehensively identify miRNAs regulating pro- and anticoagulatory components of the hemostatic system in an unbiased manner. In contrast to widely applied association and in silico studies, we made use of an integrative assay approach that combines functional aspects of miRNA silencing with unbiased physical interaction screens based on RNA pull downs coupled to next generation sequencing and finally validation by luciferase reporter experiments. This revealed a number of both gene-specific and broadly-targeting miRNAs to interact with transcripts encoding components of the plasmatic coagulation system. These results suggest that the coagulation system is controlled both by miRNAs targeting specific genes which may act as regulatory target hubs within the pathway, as well as by individual miRNAs more broadly targeting a large number of components of the pathway. These findings may also help us deciphering the role of miRNAs in the (systems) control of blood coagulation in (patho)physiological conditions, and thereby pave the ground for novel therapeutic approaches for the correction of de-regulated hemostasis in the future.» weiterlesen» einklappen