Genomic Binding and Transcriptional Regulation by the Drosophila Myc and Mnt Transcription Factors

Abstract

Deregulated expression of members of the myc oncogene family has been linked to the genesis of a wide range of cancers,whereas their normal expression is associated with growth, proliferation, differentiation, and apoptosis. Myc proteins aretranscription factors that function within a network of transcriptional activators (Myc) and repressors (Mxd/Mad and Mnt),all of which heterodimerize with the bHLHZ protein Mad and bind E-box sequences in DNA. These transcription factors recruitcoactivator or corepressor complexes that in turn modify histones. Myc, Mxd/Max, and Mnt proteins have been thoughtto act on a specific subset of genes. However, expression array studies and, most recently, genomic binding studies suggestthat these proteins exhibit widespread binding across the genome. Here we demonstrate by immunostaining of Drosophilapolytene chromosome that Drosophila Myc (dMyc) is associated with multiple euchromatic chromosomal regions. Furthermore,many dMyc-binding regions overlap with regions containing active RNA polymerase II, although dMyc can also befound in regions lacking active polymerase. We also demonstrate that the pattern of dMyc expression in nuclei overlaps withhistone markers of active chromatin but not pericentric heterochromatin. dMyc binding is not detected on the X chromosomerDNA cluster (bobbed locus). This is consistent with recent evidence that in Drosophila cells dMyc regulates rRNA transcriptionindirectly, in contrast to mammalian cells where direct binding of c-Myc to rDNA has been observed. We furthershow that the dMyc antagonist dMnt inhibits rRNA transcription in the wing disc. Our results support the view that theMyc/Max/Mad network influences transcription on a global scale.