Molecular Neurobiology

, Volume 45, Issue 3, pp 520–535

Integration of MicroRNA Databases to Study MicroRNAs Associated with Multiple Sclerosis

  • Charlotte Angerstein
  • Michael Hecker
  • Brigitte Katrin Paap
  • Dirk Koczan
  • Madhan Thamilarasan
  • Hans-Jürgen Thiesen
  • Uwe Klaus Zettl
Article

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs which regulate many genes post-transcriptionally. In various contexts of medical science, miRNAs gained increasing attention over the last few years. Analyzing the functions, interactions and cellular effects of miRNAs is a very complex and challenging task. Many miRNA databases with diverse data contents have been developed. Here, we demonstrate how to integrate their information in a reasonable way on a set of miRNAs that were found to be dysregulated in the blood of patients with multiple sclerosis (MS). Using the miR2Disease database, we retrieved 16 miRNAs associated with MS according to four different studies. We studied the predicted and experimentally validated target genes of these miRNAs, their expression profiles in different blood cell types and brain tissues, the pathways and biological processes affected by these miRNAs as well as their regulation by transcription factors. Only miRNA–mRNA interactions that were predicted by at least seven different prediction algorithms were considered. This resulted in a network of 1,498 target genes. In this network, the MS-associated miRNAs hsa-miR-20a-5p and hsa-miR-20b-5p occurred as central hubs regulating about 500 genes each. Strikingly, many of the putative target genes play a role in T cell activation and signaling, and many have transcription factor activity. The latter suggests that miRNAs often act as regulators of regulators with many secondary effects on gene expression. Our present work provides a guideline on how information of different databases can be integrated in the analysis of miRNAs. Future investigations of miRNAs shall help to better understand the mechanisms underlying different diseases and their treatments.

Keywords

Multiple sclerosis MicroRNA Databases Gene regulatory networks 

Abbreviations

CIS

Clinically isolated syndrome

CNS

Central nervous system

EAE

Experimental autoimmune encephalomyelitis

GO

Gene Ontology

miRNA

MicroRNA

MS

Multiple sclerosis

NGS

Next generation sequencing

PBMC

Peripheral blood mononuclear cells

pre-miRNA

Precursor-miRNA

pri-miRNA

Primary-miRNA

PWM

Position weight matrix

RISC

RNA-induced silencing complex

RRMS

Relapsing-remitting multiple sclerosis

SNP

Single nucleotide polymorphism

TF

Transcription factor

TFBS

Transcription factor binding site

Treg cell

T regulatory cell

Supplementary material

12035_2012_8270_MOESM1_ESM.cys (104 kb)
Online Resource 1Cytoscape session file of the miRNA interaction network. The Cytoscape network contains computationally predicted and experimentally determined interactions between MS-associated miRNAs and their putative mRNA targets. These interactions were obtained from the databases miRWalk and miRTarBase, respectively. Moreover, potential regulatory influences of transcription factors on the expression of the miRNAs were included as well. This information was taken from the miRGen 2.0 database. A visualization of the network is shown in Fig. 3. (CYS 103 kb)
12035_2012_8270_MOESM2_ESM.xls (304 kb)
Online Resource 2Table showing the grouping of similar TFBS motifs. The miRGen database provides predictions of TFBS in the promoter regions of miRNA-coding genes based on PWMs from the Transfac database. We used the web tool STAMP [76] to group similar Transfac PWMs. The Table shows, which Transfac PWMs were found to be related to each other. Predictions of similar TFBS were pooled. In total, 39 different DNA-binding patterns were distinguished and visualized in the network as TF nodes (Fig. 3, Online Resource 1). PWM = position weight matrix, TF = transcription factor, TFBS = TF binding site (XLS 304 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Charlotte Angerstein
    • 1
  • Michael Hecker
    • 1
    • 2
  • Brigitte Katrin Paap
    • 1
    • 2
  • Dirk Koczan
    • 2
  • Madhan Thamilarasan
    • 1
    • 2
  • Hans-Jürgen Thiesen
    • 2
  • Uwe Klaus Zettl
    • 1
  1. 1.Department of Neurology, Division of NeuroimmunologyUniversity of RostockRostockGermany
  2. 2.Institute of ImmunologyUniversity of RostockRostockGermany

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