Abstract
Accumulating literature documents that cancer development is strongly correlated with epigenetic change(s) such as DNA methylation and histone posttranslational modifications. Methylation on lysine 4 of H3 (H3K4me) is one of the prominent histone modification marks that correlates strongly with active transcription. A number of studies have implicated misregulation of H3K4 methylation in the pathogenesis of cancer, further emphasizing the importance of understanding the regulation of H3K4 methylation. We recently demonstrated the mechanism by which H3K4 methylation is stimulated by another histone modification, H2B monoubiquitylation (H2Bub). We took advantage of an in vitro methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the internal n-SET domain of Set1, the catalytic subunit of ySet1C, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies call attention to the n-SET domain as being a predictor of H2B ubiquitylation ‘sensing’ in bringing about downstream H3K4 methylation.