The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci 1 . Recent work suggested that rather than up-and down-regulating selected groups of genes 1-3 , Myc targets all active promoters and enhancers in the genome (a phenomenon termed "invasion") and acts as a general amplifier of transcription 4,5 . However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during Bcell lymphomagenesis in mice, in cultured B-cells and fibroblasts. Consistent with long-standing observations 6 , we detected general increases in total RNA or mRNA copies per cell (hereby termed "amplification") 4,5 when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) 7,8 or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, while having the potential to interact with all active/poised regulatory elements in the genome 4,5,9-11 , Myc does not directly act as a global *

Two opposing models have been proposed to describe the function of the MYC oncoprotein in shaping cellular transcriptomes: one posits that MYC amplifies transcription at all active loci; the other that MYC differentially controls discrete sets of genes, the products of which affect global transcript levels. Here, we argue that differential gene regulation by MYC is the sole unifying model that is consistent with all available data. Among other effects, MYC endows cells with physiological and metabolic changes that have the potential to feed back on global RNA production, processing and turnover. The field is progressing steadily towards a full characterization of the MYC-regulated genes and pathways that mediate these biological effects and - by the same token - endow MYC with its pervasive oncogenic potential.