PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

Abstract

Protein arginine methyltransferases (PRMTs) catalyze symmetric and asymmetric methylation on arginine residues of multiple protein targets including histones and have essential roles in organismal development and disease. PRMT5 mediates symmetric di-methylation (sDMA) of arginine 2 (H3R2me2s) and arginine 8 on histone 3 (H3R8me2s), arginine 3 on histones 2A and 4 (H2A/H4R3me2s) as well as several non-histone substrates like Sm proteins. Here, we found that selective inhibition of PRMT5 in mesenchymal stromal cells (MSCs) led to a reduction in colony forming units (CFUs) and increased osteoblast differentiation. PRMT5 inhibition blocked global symmetric dimethylation of H3R8 and H4R3 but not on H3R2. Genome-wide expression analysis by total RNA sequencing of mesenchymal stromal cells undergoing osteogenic differentiation revealed significant reduction in the intrinsic expression of several interferon-stimulated genes (ISGs) upon PRMT5 inhibition. Effects of PRMT5 inhibition on basal ISG expression and osteogenic differentiation was effectively blocked by exogenous activation of type I IFN signaling. Together, these results indicate important functions for PRMT5 in the regulation of basal interferon gene expression in MSCs and in the control of differentiation potential of MSCs during osteogenic differentiation.

Inhibition of PRMT5 Attenuates Oxidative Stress-Induced Pyroptosis via Activation of the Nrf2/HO-1 Signal Pathway in a Mouse Model of Renal Ischemia-Reperfusion Injury

“…Histone methyltransferases contain two primary types, namely, lysine-specific and arginine-specific. PRMTs catalyze arginine monomethylation and asymmetric or symmetric demethylation, which is a conserved and ubiquitous physiological process involved in multiple biological processes [6]. There are two types of PRMTs (i.e., type I and type II).…”

“…The protein arginine methyltransferase (PRMT) family catalyze arginine monomethylation and asymmetric or symmetric dimethylation modifications which are conserved and ubiquitous physiological processes. PRMTs play key roles in multiple biological processes [6]. There are two types of PRMTs: type I (i.e., PRMT 1, 3, and 4) catalyzing the conversion of arginine to a monomethylarginine intermediate, followed by conversion of asymmetric dimethylarginine and type II (i.e., PRMT5) catalyzing the formation of symmetric dimethylarginine [7, 8].…”

Bone Remodeling: Histone Modifications as Fate Determinants of Bone Cell Differentiation

“…PRMT5 inhibition promoted osteogenic differentiation of mesenchymal stromal cells and blocked global symmetric dimethylation of H3R8 and H4R3, but not of H3R2. These results indicate that PRMT5 controls the differentiation potential of MSCs during osteogenic differentiation [103]. Recently, PRMT1 has been described to be required for osteoclastogenesis.…”

Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648

“…PRMT5 activates RANKL-induced osteoclast differentiation, which involves the regulation of CXCL10 and RSAD2 21 . Pharmacological inhibition of Prmt5 in the ST-2 and W-20 cell lines inhibited colony-forming units and promoted osteogenesis 22 . Thus, arginine methylation is essential for the tight regulation of cell fate decision during embryonic development and homeostasis maintenance.…”