Methylation of H2AR29 is a novel repressive PRMT6 target

To understand the function of H2A modifications, we performed a systematic analysis of the histone H2A methylation status. We identified and functionally characterised two new methylation sites in H2A: R11 (H2AR11) and R29 (H2AR29). Using an unbiased biochemical approach in combination with candidate assays we showed that protein arginine methyltransferase (PRMT) 1 and PRMT6 are unique in their ability to catalyse these modifications. Importantly we found that H2AR29me2 is specifically enriched at genes repressed by PRMT6, implicating H2AR29me2 in transcriptional repression.Our data establishes R11 and R29 as new arginine methylation sites in H2A. We identified the specific modifying enzymes involved, and uncovered a novel functional role of H2AR29me2 in gene silencing in vivo. Thus this work reveals novel insights into the function of H2A methylation and in the mechanisms of PRMT6-mediated transcriptional repression.Post-translational modifications of histones play an important role in the regulation of all nuclear processes occurring on chromatin. Depending on the type of modification and/or the residue modified, they can be involved in gene activation or silencing. In particular the methylation of histones, has been extensively studied, and has been shown to regulate both processes [1]. Histones can be methylated on lysine residues by lysine methyl transferases (KMTs) and on arginine residues by protein arginine methyl transferases (PRMTs). Of the four core histones (H3, H2B, H2A and H4), methylation of the N-terminal tails of H3 and H4 has been intensively studied, whereas very little is known about modifications of H2A and H2B.Several potential methylation sites in H2A have been identified by mass spectrometry (MS) analysis, including the presence of at least two methyl groups in the first 17 amino acids of H2A [2]. However, the only methylation site of H2A that has been experimentally studied is methylation of arginine 3 (H2AR3) [3].PRMTs are involved in a var