Abstract
BackgroundThe idiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune conditions of skeletal muscle inflammation and weakness. MicroRNAs (miRNAs) are short, non-coding RNA which regulate gene expression of target mRNAs. The aim of this study was to profile miRNA and mRNA in IIM and identify miRNA-mRNA relationships which may be relevant to disease.MethodsmRNA and miRNA in whole blood samples from 7 polymyositis (PM), 7 dermatomyositis (DM), 5 inclusion body myositis and 5 non-myositis controls was profiled using next generation RNA sequencing. Gene ontology and pathway analyses were performed using GOseq and Ingenuity Pathway Analysis. Dysregulation of miRNAs and opposite dysregulation of predicted target mRNAs in IIM subgroups was validated using RTqPCR and investigated by transfecting human skeletal muscle cells with miRNA mimic.ResultsAnalysis of differentially expressed genes showed that interferon signalling, and anti-viral response pathways were upregulated in PM and DM compared to controls. An anti-Jo1 autoantibody positive subset of PM and DM (n = 5) had more significant upregulation and predicted activation of interferon signalling and highlighted T-helper (Th1 and Th2) cell pathways. In miRNA profiling miR-96-5p was significantly upregulated in PM, DM and the anti-Jo1 positive subset. RTqPCR replicated miR-96-5p upregulation and predicted mRNA target (ADK, CD28 and SLC4A10) downregulation. Transfection of a human skeletal muscle cell line with miR-96-5p mimic resulted in significant downregulation of ADK.ConclusionMiRNA and mRNA profiling identified dysregulation of interferon signalling, anti-viral response and T-helper cell pathways, and indicates a possible role for miR-96-5p regulation of ADK in pathogenesis of IIM.
Highlights
The idiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune conditions of skeletal muscle inflammation and weakness
MiRNA dysregulation has been investigated in IIM subtypes in a variety of tissues but further research is required to understand the role of microRNA in IIM pathology [5]
Expressed genes and microRNAs in IIM patients compared to controls Overall, 129, 53 and 24 differentially expressed (DE) mRNAs were identified for PM, DM and IBM compared to controls, respectively (false discovery rate (FDR) < 0.05) (Fig. 1a, Additional file 2)
Summary
The idiopathic inflammatory myopathies (IIMs) are heterogeneous autoimmune conditions of skeletal muscle inflammation and weakness. MicroRNAs (miRNAs) are short, non-coding RNA which regulate gene expression of target mRNAs. The aim of this study was to profile miRNA and mRNA in IIM and identify miRNAmRNA relationships which may be relevant to disease. The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune conditions characterised by weakness and inflammation of skeletal muscle. MicroRNAs (miRNAs) are short, non-coding, singlestranded RNAs which target particular mRNAs for translational suppression and/or degradation. In this manner miRNAs ‘fine-tune’ gene expression and influence a wide variety of cellular processes and pathways. In this study we used generation RNA sequencing to generate a comprehensive miRNA and mRNA profile in whole blood of PM, DM and IBM patients and followed up particular miRNA-mRNA interactions by transfecting a human skeletal muscle cell line with miRNA mimic
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