A homeotic mutation in the trithorax SET domain impedes histone binding

Trithorax (TRX) is a Drosophila SET domain protein that is required for the correct expression of homeotic genes. Here, we show that the TRX SET domain efficiently binds to core histones. and nucleosomes. The primary target for the SET domain is histone H3 and binding requires the N-terminal histone tails. The previously described trx(Z11) mutation changes a strictly conserved glycine in the SET domain to serine and causes homeotic transformations in the fly. We found that this mutation selectively interferes with histone binding, suggesting that histones represent a critical target during developmental gene regulation by TRX.