PRMT1 Modulates Processing of Asthma-Related Primary MicroRNAs (Pri-miRNAs) into Mature miRNAs in Lung Epithelial Cells

Abstract

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.

The Role of Protein Arginine Methyltransferase 1 in Gastrointestinal Cancers

“…Studies have found that PRMT1 is involved in the development and diseases of the nervous system and plays an important role in neurodegenerative diseases [30]. PRMT1 also promotes asthma by regulating asthma-related pri-let-7i and pri-miR-423 [31]. PRMT1-v2 activated the gluconeogenic program in hepatocytes via interactions with PGC1α, a key transcriptional coactivator regulating gluconeogenesis [32].…”

The Influence of Arginine Methylation in Immunity and Inflammation

“… 85 More recently, it was shown that PRMT1 regulates processing of asthma-related miRNAs in lung epithelial cells. 86 PRMT1 is recruited, in complex with either STAT1 or RUNX1, to promote processing of miRNAs upregulated alongside PRMT1 in patients with asthma in response to transforming growth factor beta 1 (TGF-β1). 86 These findings suggest a role for PRMT1 in acute and chronic asthma in epithelial cells and fibroblasts.…”

“… 86 PRMT1 is recruited, in complex with either STAT1 or RUNX1, to promote processing of miRNAs upregulated alongside PRMT1 in patients with asthma in response to transforming growth factor beta 1 (TGF-β1). 86 These findings suggest a role for PRMT1 in acute and chronic asthma in epithelial cells and fibroblasts. Furthermore, these findings have implications for the treatment of acute and chronic asthma as PRMT1 could serve as a specific therapeutic target.…”

“… 87 Further, elevated aDMA levels correlates with higher incidence of cardiovascular disease in these patients. 86 Autoantibodies targeting the spliceosomal, RNA-binding Sm proteins are present in the serum of SLE patients. 88 These autoantibodies recognize the symmetrically dimethylated RGG/RG epitopes of Sm proteins and p80-coilin, 89 suggesting that inhibition of PRMTs may suppress some of their ability to induce autoimmune reactions.…”

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

“…Remodeling parameters of human airway fibroblasts were also upregulated via PRMT1 and a signaling pathway involving C/EBP-β, leading to mitochondrial activity [98][99][100]. In airway epithelial cells, the processing of microRNAs might increase the susceptibility to develop asthma [101]. However, the role of the different HSPs and their variants in the context of asthma-associated airway wall remodeling is controversial and has to be further investigated [102].…”