A Histone Mutant Reproduces the Phenotype Caused by Loss of Histone-Modifying Factor Polycomb

Genetic Epigenetics Posttranslational modifications of histone proteins have been implicated in the regulation of gene transcription in organisms ranging from yeast to humans. However, epigenetic regulators can modify multiple proteins. By mutating specific histone sites in Drosophila, Pengelly et al. (p. 698) demonstrate that mutation of lysine 27 of histone H3 causes the same transcriptional defects as those observed in mutants lacking the methyltransferase PRC2 that modifies this H3 residue. These results demonstrate the functional importance of H3-K27 methylation in Polycomb repression. Furthermore, this genetic approach may be applied to investigating numerous other metazoan-specific histone modifications. Histone genetics provides functional evidence for the importance of histone modifications in gene regulation. Although many metazoan enzymes that add or remove specific modifications on histone proteins are essential transcriptional regulators, the functional significance of posttranslational modifications on histone proteins is not well understood. Here, we show in Drosophila that a point mutation in lysine 27 of histone H3 (H3-K27) fails to repress transcription of genes that are normally repressed by Polycomb repressive complex 2 (PRC2), the methyltransferase that modifies H3-K27. Moreover, differentiated H3-K27 mutant cells show homeotic transformations like those seen in PRC2 mutant cells. Taken together, these analyses demonstrate that H3-K27 is the crucial physiological substrate that PRC2 modifies for Polycomb repression.