Histone arginine methylations: their roles in chromatin dynamics and transcriptional regulation

Abstract

PRMTs (protein arginine N-methyltransferases) specifically modify the arginine residues of key cellular and nuclear proteins as well as histone substrates. Like lysine methylation, transcriptional repression or activation is dependent upon the site and type of arginine methylation on histone tails. Recent discoveries imply that histone arginine methylation is an important modulator of dynamic chromatin regulation and transcriptional controls. However, under the shadow of lysine methylation, the roles of histone arginine methylation have been under-explored. The present review focuses on the roles of histone arginine methylation in the regulation of gene expression, and the interplays between histone arginine methylation, histone acetylation, lysine methylation and chromatin remodelling factors. In addition, we discuss the dynamic regulation of arginine methylation by arginine demethylases, and how dysregulation of PRMTs and their activities are linked to human diseases such as cancer.

Figure 1. Role of PRMTs in cellular processes

PRMTs are found in both the cytoplasm and the nucleus. PRMT1 is found in higher concentrations in the cytoplasm than in the nucleus. Only PRMT6 is found exclusively in the nucleus. Arginine methylation of protein modulates several cellular processes, including signal transduction, transcriptional regulation, DNA repair and RNA processing. The red lines indicate modifications that are inhibitory. The green lines indicate modifications that are stimulatory. Green circles labelled Me indicate a protein modified by a PRMT. ER, oestrogen receptor; 53BP1, p53-binding protein 1; 40S/rpS2, 40S ribosomal protein S2; SPT5, Suppressor of Ty 5; TAT, HIV transactivator; TF, transcription factor.

Figure 2. Arginine methylation by PRMTs

Both type I and type II enzymes produce monomethylarginine. Asymmetrical dimethylated arginine is generated by type I enzymes, and symmetrical dimethylarginine is generated by type II enzymes. AdoHey, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine.

Figure 3. Family of PRMT enzymes

There are currently 11 members of the PRMT family that share conserved catalytic domains (black). PRMT9 has four isoforms. PRMT7 and PRMT10 harbour two catalytic domains. The histone substrate of each enzyme, the type of modification that it catalyses, and the biological functions of modification are shown. DNMT3, DNA methyltransferase 3; ER, oestrogen receptor.

Figure 4. Histone arginine demethylation

(A) PAD4 can convert methylated or unmethylated arginine to citrulline. The reaction then blocks arginine methylation from occurring on histone tails. (B) JMJD6 is an Fe(II)- and 2-oxoglutarate (α-KG)-dependent dioxygenase which removes methyl groups from symmetrical dimethyl H4R3 (SDMA) or asymmetrical dimethyl H4R3 (ADMA) to generate monomethylarginine (H4R3me1).

Figure 5. Cross-regulation between arginine methylation and histone lysine acetylation on histone H3 and H4 tails

Asymmetrical or symmetrical dimethylation of H4R3 can either potentiate or inhibit H4 tail acetylation (Ac) respectively. Methylation of H3R2 by PRMT6 negatively controls the deposition of H3K4 trimethylation. In contrast, H3K18 and H3K23 acetylation stimulates methylation of H3R17 by CARM1. aMe, asymmetrical methylation; sME, symmetrical methylation.

Figure 6. Transcriptional activation of hormone-response genes via arginine methylation

The picture illustrates a simplified model of the transcriptional activation of a hormone-response gene. PRMT1 and CARM1 are important regulators of the hormone-response genes. One of the first steps in transcriptional activation is asymmetrical dimethylation of H4R3 by PRMT1. This is followed by acetylation of H4K8, H4K12 and H4K16 by HATs (histone acetyltransferases), as well as acetylation of H3K18 and H3K23 by CBP/p300. Acetylation of H3K18 and H3K23 is preceded by asymmetrical dimethylation of H3R17 by CARM1. This results in an increase in the number of transcripts. Subsequent recruitment of SWI/SNF complex further increases the specificity/activity of CARM1 on nucleosomal substrates and remodels chromatin to facilitate the formation of transcription complexes. CARM1 also methylates the KIX domain of CBP. This methylation acts to inhibit the activity of the HAT complex and to initiate the process of transcriptional deactivation [26]. HRE, hormone-responsive enhancer element; Me, methylation; NR, nuclear hormone receptor; POLII, RNA polymerase II; TBP, TATA-box-binding protein; TFIIB, transcription factor IIB.

Figure 7. Transcriptional repression by PRMT5 and PRMT6

(A) The picture depicts a model of the transcriptional repression of Hox genes and Myc-target genes, cad and nuc, by PRMT5 [67]. PRMT5 is associated with the hSWI/SNF complex. PRMT5 catalyses the symmetrical dimethylation of H4R3 and H3R8 (denoted by red circles labelled Me R3 and Me R8). Symmetrical dimethylation of H3R8 is associated with deacetylation of histones H3 and H4 (denoted by the grey circle labelled K9). (B) The picture depicts a model of the transcriptional repression of Hox genes and Myc-dependent genes by PRMT6 [35,68]. Asymmetrical dimethylation of H3R2 (denoted by the red circle labelled Me R2) is mutually exclusive of the di- and tri-methylation of H3K4 (denoted by the green circle labelled Me K4). The presence of asymmetrical dimethylation of H3R2 inhibited binding of the Ash2 (absent, small, or homeotic disc 2)/WDR5 (WD40 repeat-containing protein 5)/MLL-family methyltransferase complex and methylation of H3K4. Brg1, BRM-related gene 1; mSin3A; mammalian SIN3A; HDAC2, histone deacetylase 2; RpBP5, retinoblastoma binding protein 5.