GSE132407
PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2 (RNA-seq)
Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks generally associated with transcriptional repression. However, we found that PRMT5 inhibition (or depletion) led to more genes being down-regulated than up-regulated, 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 down-regulated by PRMT5 inhibition, suggesting that the increased H3K27me3 contributes to the transcription repression of these genes. Interestingly, the growth inhibitory effect of PRMT5 inhibition was also partially rescued by combined treatment with EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects. Overall design: Molm13 cells were treated with DMSO, EZH2 inhibitor, PRMT5 inhibitor or combination of both inhibitors for 4 days. Total RNA were purified with RNeasy plus mini kit. Libraries were prepared using standard Illumina protocols with paired RNA sequencing.