Schematic and simplified depiction of the interaction of MYC with ASH2L–KMT2 complexes and their effects on core histone modifications and gene transcription. In the repressed state, characterized by H3K27me3, no ASH2L–KMT2 complexes are bound to chromatin. In open chromatin, specific promoters are associated with ASH2L–KMT2 complexes resulting in high H3K4me3. Two forms of open chromatin are indicated, one is characterized by H3K27me3 in addition to H3K4me3. This is referred to as bivalent chromatin and promoters with these two marks are typically poised. How ASH2L–KMT2 complexes are recruited initially is not well understood. This may occur through direct interaction of the KMT2 complex with chromatin or through an unknown transcription factor (referred to as X). KDM6 enzymes, which demethylate H3K27, and CBP/p300, which acetylate H3K27, have been reported to interact with KMT2 complexes and may therefore be located on promoters prior to MYC binding. In the absence of MYC, H3K27 modifying enzymes seem to be largely inactive. Promoters switch to a transcriptionally active mode upon binding of MYC, which we postulate to result in the activation of these H3K27 modifying enzymes (indicated by the color change). This leads to a reduction of H3K27me3 and concomitant increase in H3K27ac, which combined with H3K4me3 marks open chromatin with active gene transcription.