Caf1 regulates Ash1 histone methyltransferase activity via sensing unmodified histone H3.

Histone modifications are one of key mechanisms to regulate gene expression. Ash1 is a histone H3K36 methyltransferase and involved in gene activation. Ash1 forms a large complex with Mrg15 and Caf1/p55/Nurf55/RbAp48 (AMC complex). Ash1 subunit alone has very low activity due to the auto-inhibition and the binding of Mrg15 releases the auto-inhibition. Caf1 is a scaffolding protein commonly found in several chromatin modifying complexes. Caf1 has an ability to sense unmodified histone H3K4 residue. However, the role of Caf1 in AMC complex has not been investigated. Here, we dissected the interaction among the AMC complex subunits, revealing that Caf1 uses the histone H4 binding pocket to interact with Ash1 near the histone binding module cluster. Furthermore, we show that H3K4 methylation inhibits AMC HMTase activity via Caf1 sensing unmodified histone H3K4 to regulate the activity in an inter-nucleosomal manner, suggesting that there is a crosstalk between H3K4 and H3K36 methylations. Our work reveals a delicate regulatory mechanism of AMC histone H3K36 methyltransferase complex.