PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2

Abstract

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

Protein Arginine Methyltransferase 5 Functions via Interacting Proteins

“…In acute lymphoblastic leukemia (ALL), PRMT5 promotes the proliferation of lymphocytes by inhibiting apoptosis, and the down-regulation of H4R3sme2 by PRMT5 silencing induced ALL differentiation from the pre-B to immature B stage (Mei and Zhang, 2019). In addition, the inhibition of PRMT5-mediated H3K27 methylation contributes to cell cycle progression (Liu F. et al, 2020).…”

PRMT5 function and targeting in cancer

“…Indeed, PRMT5 depletion or inhibition downregulates roughly 50% of genes that exhibit 2-fold change (~1,300 genes) in AML, of which 53% (335 genes) restored expression upon inhibition of the H3K27 methyltransferase, EZH2. Further, H3K27me3 at the transcription start site of 25% of the 335 genes was reversed upon EZH2 inhibition [27]. These findings further highlight PRMT5-dependent regulation of gene expression.…”

PRMT5 Is Involved in Spermatogonial Stem Cells Maintenance by Regulating Plzf Expression via Modulation of Lysine Histone Modifications

“…PRMT5-induced H4R3 methylation has been reported to regulate lysine methylation modification (H3K27) via recruitment of Polycomb protein in a Pax2/Grg4-dependent manner ( Patel et al, 2012 ). In hematopoietic cells, Prmt5 depletion resulted in the upregulation of global H3K27 dimethylation and trimethylation ( Liu F. et al, 2020 ). In the present study, the global level of H3K27me2 was significantly increased, whereas the level of H3K27me3 was not increased in Prmt5 -deficient SSCs ( Figures 6A,B ).…”