Abstract A44: Selective transcriptional regulation by Myc in growth control and tumorigenesis

Myc binds DNA with a preference for the E-box consensus CACGTG. In vivo, however, DNA recognition is primarily determined by chromatin context, preceding sequence-specific DNA binding. Myc preferentially associates with active/poised promoters and, to a lesser extent, distal enhancer elements. When expressed at high levels, Myc targets virtually all active promoters and enhancers in the genome, a phenomenon termed “invasion”, which contributed to the concept that Myc acts as a general amplifier of transcriptional activity (1, 2). We recently presented data that support a different scenario (3). While Myc has the potential to interact with all active/poised regulatory elements in the genome, this does not systematically lead to a productive regulatory interaction: instead, promoter/enhancer invasion by Myc most likely reflects the detection of low-affinity interactions (protein-protein or protein-DNA) that allow the transcription factor to target the relevant genomic regions, preceding local scanning of the DNA sequence for high-affinity binding sites (4). Most importantly, when productively engaged by Myc, target genes can be either induced or repressed, as shown in different cell types (3, 5). Our data also show that the global increase in mRNA copies per cell (or amplification), observable either during tumor progression or upon mitogenic stimulation of normal cells, can occur in the absence of overt promoter/enhancer invasion by Myc. RNA amplification is thus indirect, most likely attributable to changes in physiological features that impact on global RNA production and turnover (e.g. cell size, energy metabolism, etc..). Consistent with this view, many Myc-regulated genes have - or may have - central roles in these physiological processes. Putting together all available data, the emerging unifying model supports a central role for Myc in the control of cellular physiology and metabolism, including - albeit indirectly - global RNA production and turnover. An important challenge lying ahead is the full characterization of the Myc-regulated genes and pathways that mediate these biological effects and - by the same token - endow Myc with such pervasive oncogenic potential. 1. Lin CY, et al. (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151:56-67. 2. Nie Z, et al. (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151:68-79. 3. Sabo A, et al. (2014) Selective transcriptional