Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor γ-dependent macrophage differentiation

Abstract

Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in protein arginine methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses , we created a cell type-specific knock-out mouse model. We showed that myeloid-specific PRMT1 knock-out mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture. We found that this defect is because of defective peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 macrophage differentiation. PPARγ is one of the key transcription factors regulating macrophage polarization toward a more anti-inflammatory and pro-resolving phenotype. We found that PRMT1 knock-out macrophages failed to up-regulate PPARγ expression in response to IL4 treatment resulting in 4-fold lower PPARγ expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARγ gene expression through histone H4R3me2a methylation at the PPARγ promoter. Supplementing with PPARγ agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiation and and abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARγ expression contributes to the infection susceptibility in PRMT1 knock-out mice.

The polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinoma

“…Recently we and others have found that PRMT1 is an immune regulator. Its targets include, but are not limited to, TRAF6, NFκB, PPARγ, c-Myc, STAT3, FOXOs and β-catenin all of which are involved in immune cell regulation, specifically immune cell polarization (7,9,10,21). Thus, it is not surprising that PRMT1 is involved in regulation of the tumor immune environment.…”

“…Our previous work has demonstrated that PRMT1 is an important regulator of immune signaling in multiple cell types including monocytes, liver macrophages, hepatocytes, liver tumor associated macrophages and hepatoma cells (8)(9)(10)18). In human HCC, PRMT1 overexpression is associated with poor prognosis ( Figure S3), suggesting that PRMT1 might promote tumor growth.…”

“…This induction results in the deposition of the PRMT1 dependent histone mark H4R3me2a on several promoters involved in M2-like differentiation including PPARγ promoter. Data from PRMT1 knockout mice show that PRMT1 deficiency results in diminished PPARγ expression and lack of PPARγ-dependent M2 differentiation (9). In human livers PRMT1 is involved in macrophage polarization and tumor associated macrophage phenotype and function (10).…”

Protein arginine methyl transferase 1– and Jumonji C domain‐containing protein 6–dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice

“…C57BL/6NTac‐Prmt1 tm1a(EUCOMM)Wtsi /WtsiCnbc mice were obtained from EUCOMM (EUCOMM project: 40181) and bred with Flp recombinase mice to get homozygous Prmt1 floxed breeders as decribed . These mice were next crossed with Albumin‐Cre mice to generate mice lacking Prmt1 in hepatocytes.…”

“…Chromatin immunoprecipitation (ChIP) was performed as described . Mouse liver tissue was homogenized, then cross‐linked by the addition of 1% formaldehyde for 10 minutes.…”