Anyetei-Anum, C. S.; Leatham-Jensen, M. P.; Fox, G. C.; Smith, B. R.; Krajewski, K.; Strahl, B. D.; Dowen, J.; Matera, A. G.; Duronio, R. J.; McKay, D. J.

Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb and trithorax complexes determine the ON/OFF state of targets like the Hox genes. Trithorax encodes a methyltransferase specific to histone H3 lysine-4 (H3K4). However, there is no direct evidence that H3K4 regulates Polycomb group target genes in vivo. Here, we demonstrate two key roles for replication-dependent histone H3.2K4 in target control. We find that H3.2K4 antagonizes Polycomb group catalytic activity and that it is required for proper target gene activation. We conclude that H3.2K4 directly regulates expression of Polycomb targets.