Arginine methylation regulates c-Myc–dependent transcription by altering promoter recruitment of the acetyltransferase p300

Abstract

Protein arginine methyltransferase 1 (PRMT1) is an essential enzyme controlling about 85% of the total cellular arginine methylation in proteins. We have shown previously that PRMT1 is an important regulator of innate immune responses and that it is required for M2 macrophage differentiation. c-Myc is a transcription factor that is critical in regulating cell proliferation and also regulates the M2 transcriptional program in macrophages. Here, we sought to determine whether c-Myc in myeloid cells is regulated by PRMT1-dependent arginine methylation. We found that PRMT1 activity was necessary for c-Myc binding to the acetyltransferase p300. PRMT1 inhibition decreased p300 recruitment to c-Myc target promoters and increased histone deacetylase 1 (HDAC1) recruitment, thereby decreasing transcription at these sites. Moreover, PRMT1 inhibition blocked c-Myc-mediated induction of several of its target genes, including peroxisome proliferator-activated receptor γ () and mannose receptor C-type 1 (), suggesting that PRMT1 is necessary for c-Myc function in M2 macrophage differentiation. Of note, in primary human blood monocytes, p300-c-Myc binding was strongly correlated with PRMT1 expression, and in liver sections, PRMT1, c-Myc, and M2 macrophage levels were strongly correlated with each other. Both PRMT1 levels and M2 macrophage numbers were significantly lower in livers from individuals with a history of spontaneous bacterial peritonitis, known to have defective cellular immunity. In conclusion, our findings demonstrate that PRMT1 is an important regulator of c-Myc function in myeloid cells. PRMT1 loss in individuals with cirrhosis may contribute to their immune defects.

Transcriptome Profiling of Bovine Macrophages Infected by Mycobacterium avium spp. paratuberculosis Depicts Foam Cell and Innate Immune Tolerance Phenotypes

“…The 4.0fold change of IL10 at 8 hpi was confirmed by qPCR (p < 0.0001; Table 2). The gene expression of protein arginine methyltransferase 1 (PRMT1), whose activity is necessary for the proto-oncogene c-Myc function in M2 macrophage differentiation (48), and MYC was slightly increased at 8 hpi (2.0-and 3.2-fold change, respectively) in MAP-infected JD(-) macrophages ( Supplementary Table 4). Overall, some M1 and M2 marker genes were upregulated by MAP, while a dominant metabolic profile promoting glycolysis seemed to prevail during the early stage of the infection.…”

“…In addition to the transcriptional activator KLF4, c-Myc is also involved in the formation of cytoplasmic lipid droplets (64). The activity of PRMT1 is necessary for c-Myc transcriptional function in M2 polarization (48) and they were increased in MAP-infected JD(-) macrophages. Altogether, their effects associated with M2 polarization and lipid accumulation also support a role in the development of the foamy shape observed in response to MAP infection (Figure 3).…”

Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

“…Ding et al, 61 Subat et al 62 ↓ ? ↓ DNA hypermethylation Tikhanovich et al, 66,67 Zhao et al 68 PRMT1 ↑ M2 polarization↑ ↑ histone H4R3me2a methylation of PPARγ…”

“…63 Most importantly, there is increased attention on histone modifications that impact hepatic macrophage functional responses and M1/M2 polarization by modulating cellular signaling and signature gene expression. 64,65 Protein arginine methyltransferase 1 (PRMT1) is known to be an important regulator of inflammatory responses 66 and is required for favoring an anti-inflammatory M2 phenotype through histone H4R3me2a methylation of the PPARγ promoter. 67 Moreover, PRMT1-dependent arginine methylation is necessary for c-Myc function in M2 differentiation, resulting from c-Myc binding to the acetyltransferase p300 and from a decrease in histone deacetylase 1 (HDAC1) recruitment.…”

Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer

“…Once the expression level of c-Myc is out of control, it can lead to tumorigenesis. c-Myc regulates its target genes by directly binding or recruiting histone modification enzyme to the gene’s promoter region [ 22 , 23 ]. The predicted c-Myc binding sites in FoxM1’s promoter suggested its regulatory role for FoxM1 expression.…”