Methylation of histone H3 and H4 by PRMT5 regulates ribosomal RNA gene transcription

Abstract

In an effort to understand the epigenetic regulation of ribosomal RNA gene (rDNA) expression we have previously demonstrated the role of DNA methyltransferases and methyl CpG binding proteins in rRNA synthesis. Here, we studied the role of protein arginine methyltransferase PRMT5 and the two methylated histones H3R8Me2 and H4R3Me2, in rDNA expression in Epstein Barr virus- transformed primary B-cells (LCLs) and in HeLa cells responding to serum-regulated growth. Chromatin immunoprecipitation assay showed that histones H3 and H4 associated with rRNA promoters were differentially methylated at arginine residues 8 and 3, respectively, depending on its transcriptional activity. Association of PRMT5 and methylated H3 with the unmethylated promoters in resting B-cells was significantly reduced in rapidly growing LCLs. Unlike PRMT5 and H3R8Me2, histone H4 associated with both methylated and unmethylated rRNA promoters in resting B-cells was methylated at the R3 residue. However, a dramatic decrease in R3 methylation of H4 recruited to the unmethylated rRNA promoters was observed in LCLs while it remained unaltered in the fraction bound to the methylated promoters. Differential interaction of PRMT5 and methylation of H3 and H4 associated with the rRNA promoters was also observed when serum starved HeLa cells were allowed to grow in serum replenished media. Ectopic expression of PRMT5 suppressed activity of both unmethylated and methylated rRNA promoter in transient transfection assay whereas siRNA mediated knockdown of PRMT5 increased rRNA synthesis in HeLa cells. These data suggest a key role of PRMT5 and the two methylated histones in regulating rRNA promoter activity.

ArabidopsisFloral Initiator SKB1 Confers High Salt Tolerance by Regulating Transcription and Pre-mRNA Splicing through Altering Histone H4R3 and Small Nuclear Ribonucleoprotein LSM4 Methylation

“…Transcription is largely regulated by histone modifications. The histone mark H4R3sme2, catalyzed by SKB1 or its homolog PRMT5, suppresses gene transcription, which is supported by the observation that decreasing H4R3sme2 levels increase gene transcription by disrupting SKB1 (Pal et al, 2004;Wang et al, 2007;Schmitz et al, 2008;Zhao et al, 2009;Majumder et al, 2010). When plants are exposed to high concentrations of salt and ABA, SKB1 disassociates from chromatin to reduce H4R3sme2 levels and the resulting high expression of genes in ABA signaling and salt response (Figures 3 and 4).…”

In situ histone landscape of nephrogenesis

“…H3R8me2 is associated with transcriptional repression of ribosomal genes and of tumor suppressors in cancer cells. 36,49,50 The potential significance of histone arginine methylation in nephrogenesis remains to be determined, since relatively little is known about the functions of these chromatin marks.…”

“…17 H3R2me2s is a repressive histone modification, 33,34 whereas and H3R8me2as may mediate either activation or repression. [35][36][37] H3R17me2as is generally an activating mark. 38,39 Interestingly, there was a differential enrichment of these three histone marks, since H3R2me2 and H3R17me2 are abundantly expressed in the cap mesenchyme and nascent nephrons, whereas H3R8me2 is more enriched in nascent nephrons (Fig.…”

The Epigenetic Pathways to Ribosomal DNA Silencing

“…This noncoding RNA is upregulated in growtharrested cells and is accompanied by increased SUV4-20H2-mediated H4K20me3 and chromatin compaction (80,81). Additionally, PRMT5, the type II arginine methyltransferase that catalyzes monomethylation or symmetric dimethylation of histones H3 and H4, plays a key role in silencing rDNA when the cells are in a stationary or nonproliferating state (82).…”