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Published on: June 24, 2014
Circulating miRNome profiling in Moyamoya disease-discordant monozygotic twins and endothelial microRNA expression
Haruto Uchino1, Masaki Ito2, Ken Kazumata1
1Department of Neurosurgery, Hokkaido University Graduate School of Medicine, North 15 West 7, Sapporo, 0608638, Japan.
Background:
Moyamoya disease (MMD) is characterized by progressive stenosis of intracranial arteries in the circle of Willis with unknown etiology even after the identification of a Moyamoya susceptible gene, RNF213. Recently, differences in epigenetic regulations have been investigated by a case-control study in MMD. Here, we employed a disease discordant monozygotic twin-based study design to unmask potential confounders.
Methods:
Circulating genome-wide microRNA (miRNome) profiling was performed in MMD-discordant monozygotic twins, non-twin-MMD patients, and non-MMD healthy volunteers by microarray followed by qPCRvalidation, using blood samples. Differential plasma-microRNAs were further quantified in endothelial cells differentiated from iPS cell lines (iPSECs) derived from another independent non-twin cohort. Lastly, their target gene expression in the iPSECs was analyzed.
Results:
Microarray detected 309 plasma-microRNAs in MMD-discordant monozygotic twins that were also detected in the non-twin cohort. Principal component analysis of the plasma-microRNA expression level demonstrated distinct 2 groups separated by MMD and healthy control in the twin- and non-twin cohorts. Of these, differential upregulations of hsa-miR-6722-3p/- 328-3p were validated in the plasma of MMD (absolute log2 expression fold change (logFC) > 0.26 for the twin cohort; absolute logFC > 0.26, p < 0.05, and q < 0.15 for the non-twin cohort). In MMD derived iPSECs, hsa-miR-6722-3p/- 328-3p showed a trend of up-regulation with a 3.0- or higher expression fold change. Bioinformatics analysis revealed that 41 target genes of miR-6722-3p/- 328-3p were significantly down-regulated in MMD derived iPSECs and were involved in STAT3, IGF-1-, and PTEN-signaling, suggesting a potential microRNA-gene expression interaction between circulating plasma and endothelial cells.
Conclusions:
Our MMD-discordant monozygotic twin-based study confirmed a novel circulating microRNA signature in MMD as a potential diagnostic biomarker minimally confounded by genetic heterogeneity. The novel circulating microRNA signature can contribute for the future functional microRNA analysis to find new diagnostic and therapeutic target of MMD.
Insights
This study identified a novel circulating microRNA signature in Moyamoya disease (MMD) patients. This signature, including hsa-miR-6722-3p and hsa-miR-328-3p, shows potential as a diagnostic biomarker for MMD.
Area of Science:
- Genetics and Epigenetics
- Vascular Neurology
- Biomarker Discovery
Background:
- Moyamoya disease (MMD) is a progressive stenosis of intracranial arteries with unknown etiology, despite the identification of the RNF213 gene.
- Epigenetic dysregulation is increasingly investigated in MMD pathogenesis.
- A disease-discordant monozygotic twin study design was employed to minimize genetic confounding factors.
Purpose of the Study:
- To identify circulating microRNA (miRNA) signatures associated with Moyamoya disease (MMD).
- To investigate the potential of these miRNAs as diagnostic biomarkers for MMD.
- To explore the relationship between plasma miRNAs and endothelial cell gene expression in MMD.
Main Methods:
- Genome-wide plasma microRNA profiling using microarray and qPCR validation in MMD-discordant monozygotic twins and non-twin cohorts.
- Quantification of differential plasma-miRNAs in induced pluripotent stem cell-derived endothelial cells (iPSECs) from an independent cohort.
- Analysis of target gene expression in MMD-derived iPSECs to understand miRNA-gene interactions.
Main Results:
- Distinct plasma microRNA profiles were observed between MMD patients and healthy controls in both twin and non-twin cohorts.
- Upregulation of hsa-miR-6722-3p and hsa-miR-328-3p was validated in MMD plasma.
- These miRNAs showed a trend of upregulation in MMD-derived iPSECs, with 41 target genes significantly downregulated, implicating STAT3, IGF-1, and PTEN signaling pathways.
Conclusions:
- A novel circulating microRNA signature, including hsa-miR-6722-3p and hsa-miR-328-3p, was confirmed in Moyamoya disease (MMD).
- This signature serves as a potential diagnostic biomarker for MMD, with minimal confounding from genetic heterogeneity.
- The findings support future functional miRNA analysis for novel diagnostic and therapeutic targets in MMD.
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