Integrated analysis of microRNA regulation and its interaction with mechanisms of epigenetic regulation in the etiology of systemic lupus erythematosus

Abstract

The aim of this study was to identity in silico the relationships among microRNAs (miRNAs) and genes encoding transcription factors, ubiquitylation, DNA methylation, and histone modifications in systemic lupus erythematosus (SLE). To identify miRNA dysregulation in SLE, we used miR2Disease and PhenomiR for information about miRNAs exhibiting differential regulation in disease and other biological processes, and HMDD for information about experimentally supported human miRNA-disease association data from genetics, epigenetics, circulating miRNAs, and miRNA-target interactions. This information was incorporated into the miRNA analysis. High-throughput sequencing revealed circulating miRNAs associated with kidney damage in patients with SLE. As the main finding of our in silico analysis of miRNAs differentially expressed in SLE and their interactions with disease-susceptibility genes, post-translational modifications, and transcription factors; we highlight 226 miRNAs associated with genes and processes. Moreover, we highlight that alterations of miRNAs such as hsa-miR-30a-5p, hsa-miR-16-5p, hsa-miR-142-5p, and hsa-miR-324-3p are most commonly associated with post-translational modifications. In addition, altered miRNAs that are most frequently associated with susceptibility-related genes are hsa-miR-16-5p, hsa-miR-374a-5p, hsa-miR-34a-5p, hsa-miR-31-5p, and hsa-miR-1-3p.

Fig 1. Cluster miRNAS: Dendrogram of results of cluster analysis of miRNAs related to SLE patients.

This is the result from the interrogation of different databases in which the disease was associated with the regulation of these miRNAS, directly created from DIANA-miRPath v3.0 interface (http://www.microrna.gr/miRPathv3).

Fig 2. Heatmap of SLE: A miRNA versus GO Slim category heatmap directly created from DIANA-miRPath v3.0 interface.

The heatmap depicts the level of enrichment of GO categories of several miRNAs in SLE patients, and enables the identification of miRNA subclasses or GO terms that characterize similar miRNAs because they are clustered together (http://www.microrna.gr/miRPathv3).

Fig 3. Networks of miRNAS with regular expression in patients with SLE and the associated proteins post-translational modifications (PTMs) coding genes.

Green sphere corresponds to the name of the associated proteins post-translational modifications (PTMs) and gray spheres are miRNAS. On the other hand, arrows show regulation by miRNAS to the mRNA of associated proteins post-translational modifications (PTMs) coding genes.

Fig 4

Regulatory network in miRNAs of patients with SLE (Blue rectangles), associated SLE genes, and genes associated with post-translational modifications (Pink rectangles). Black lines represent protein–miRNA interactions and red lines represent protein-protein interactions.