Targeting MYC to chromatin. The figure shows four ways that MYC can be targeted to its genomic sites in vivo. (a) The classic view. In this model, binding of MYC/MAX dimers to DNA is signaled primarily through sequence-specific recognition of the E-box by the BR-HLH-LZ regions of each protein (Figure 4). (b) Effect of chromatin context. In this model, MYC/MAX dimers will only bind E-boxes within a permissive chromatin environment, marked by the presence of CpG islands and active histone modifications such as H3-K4 methylation (me). (c) Effect of MYC dosage. At low levels of MYC (top panel), MYC/MAX dimers bind primarily to promoter proximal canonical E-boxes. At high levels of MYC, MYC/MAX dimers bind E-boxes at distal enhancer sequences and also recognize imperfect E-box sequences (“iE”). (d) Recruitment by other transcription factors. In this image, MYC/MAX dimers are recruited by the retinoic acid receptor-α (RAR) to its cognate DNA element (RARE) to regulate entirely new sets of genes. Note that interaction with RARα does not account for all or likely most of the E-box independent binding of MYC that has been reported. Also note that these mechanisms are not mutually exclusive.