Trimethylation of Histone H3 Lysine 36 by Human Methyltransferase PRDM9 Protein

Background: Histone methyltransferase PRDM9 marks recombination hot spots and is implicated in sterility and cancers. Results: We identified histone H3K36 as a new methylation mark for PRDM9. Conclusion: PRDM9 is a highly active histone methyltransferase that trimethylates H3K4 and H3K36. Significance: Discovering PRDM9 as a H3K36 methyltransferase could lead to identifying the roles that PRDM9 may play in human fertility and susceptibility to cancer. PRDM9 (PR domain-containing protein 9) is a meiosis-specific protein that trimethylates H3K4 and controls the activation of recombination hot spots. It is an essential enzyme in the progression of early meiotic prophase. Disruption of the PRDM9 gene results in sterility in mice. In human, several PRDM9 SNPs have been implicated in sterility as well. Here we report on kinetic studies of H3K4 methylation by PRDM9 in vitro indicating that PRDM9 is a highly active histone methyltransferase catalyzing mono-, di-, and trimethylation of the H3K4 mark. Screening for other potential histone marks, we identified H3K36 as a second histone residue that could also be mono-, di-, and trimethylated by PRDM9 as efficiently as H3K4. Overexpression of PRDM9 in HEK293 cells also resulted in a significant increase in trimethylated H3K36 and H3K4 further confirming our in vitro observations. Our findings indicate that PRDM9 may play critical roles through H3K36 trimethylation in cells.