An early Myc-dependent transcriptional program underlies enhanced macromolecular biosynthesis and cell growth during B-cell activation

Abstract

Upon activation, lymphocytes exit quiescence and undergo substantial increases in cell size, accompanied by activation of energy-producing and anabolic pathways, widespread chromatin decompaction and elevated transcriptional activity. These changes depend upon prior induction of the Myc transcription factor, but how Myc controls them remains unclear. We addressed this issue in primary mouse B-cells, based on conditional deletion of the c-myc gene, followed by LPS stimulation. Myc was rapidly induced, became detectable on virtually all active promoters and enhancers, but had no direct impact on global transcriptional activity. Instead, Myc contributed to the swift up- and down-regulation of several hundred genes, including many known regulators of the aforementioned cellular processes. Myc-activated promoters were enriched for E-box consensus motifs, bound Myc at the highest levels and showed enhanced RNA Polymerase II recruitment, the opposite being true at down-regulated loci. Remarkably, the Myc-dependent signature identified in activated B-cells was also enriched in Myc-driven B-cell lymphomas: hence, besides modulation of new cancer-specific programs, the oncogenic action of Myc may largely rely on sustained deregulation of its normal physiological targets.