Protein arginine methyltransferase-1 (PRMT1) is an important epigenetic regulator of cell function and contributes to inflammation and remodeling in asthma in a cell type-specific manner. Disease-specific expression patterns of microRNAs (miRNA) are associated with chronic inflammatory lung diseases, including asthma. The de novo synthesis of miRNA depends on the transcription of primary miRNA (pri-miRNA) transcript. This study assessed the role of PRMT1 on pri-miRNA to mature miRNA process in lung epithelial cells. Human airway epithelial cells, BEAS-2B, were transfected with the PRMT1 expression plasmid pcDNA3.1-PRMT1 for 48 h. Expression profiles of miRNA were determined by small RNA deep sequencing. Comparing these miRNAs with datasets of microarrays from five asthma patients (Gene Expression Omnibus dataset), 12 miRNAs were identified that related to PRMT1 overexpression and to asthma. The overexpression or knockdown of PRMT1 modulated the expression of the asthma-related miRNAs and their pri-miRNAs. Coimmunoprecipitation showed that PRMT1 formed a complex with STAT1 or RUNX1 and thus acted as a coactivator, stimulating the transcription of pri-miRNAs. Stimulation with TGF-b1 promoted the interaction of PRMT1 with STAT1 or RUNX1, thereby upregulating the transcription of two miRNAs: let-7i and miR-423. Subsequent chromatin immunoprecipitation assays revealed that the binding of the PRMT1/STAT1 or PRMT1/RUNX1 coactivators to primary let-7i (pri-let-7i) and primary miR (pri-miR) 423 promoter was critical for pri-let-7i and pri-miR-423 transcription. This study describes a novel role of PRMT1 as a coactivator for STAT1 or RUNX1, which is essential for the transcription of pri-let-7i and pri-miR-423 in epithelial cells and might be relevant to epithelium dysfunction in asthma.
SummaryTherapeutic administration of recombinant proteins has been used for the treatment of various diseases in multiple studies. Herein, we investigated the function of the acute phase protein Orosomucoid 2 (Orm2), which is mainly secreted by hepatocytes, and evaluated its potential as a therapeutic strategy for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We here revealed that a high expression of Orm2 protected mice from high-fat diet (HFD)-induced obesity. The pharmacological administration of recombinant ORM2 protein attenuated hepatic steatosis, inflammation, hepatocyte injury, and fibrosis in mouse livers, which suffered NAFLD and NASH under dietary challenge conditions. Orm2 knockout mice spontaneously underwent obese after 16 weeks under normal diet. Orm2 deficiency exacerbated HFD-induced steatosis, steatohepatitis, and fibrosis in mice. Mechanistically, the deletion of Orm2 led to the activation of the Erk1/2-PPARγ-Cd36 signaling pathway, which in turn increased fatty acid uptake and absorption in hepatocytes and mice. Collectively, our results provide Orm2 is an essential factor for preventing NASH and associated NAFLD under obesity.
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