Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation

Abstract

The Myc protein binds DNA and activates transcription by mechanisms that are still unclear. We used chromatin immunoprecipitation (ChIP) to evaluate Myc-dependent changes in histone acetylation at seven target loci. Upon serum stimulation of Rat1 fibroblasts, Myc associated with chromatin, histone H4 became locally hyperacetylated, and gene expression was induced. These responses were lost or severely impaired in Myc-deficient cells, but were restored by adenoviral delivery of Myc simultaneous with mitogenic stimulation. When targeted to chromatin in the absence of mitogens, Myc directly induced H4 acetylation. In addition, Myc recruited TRRAP to chromatin, consistent with a role for this cofactor in histone acetylation. Finally, unlike serum, Myc alone was very inefficient in inducing expression of most target genes. Myc therefore governs a step, most likely H4 acetylation, that is required but not sufficient for transcriptional activation. We propose that Myc acts as a permissive factor, allowing additional signals to activate target promoters.

A role for Myc in facilitating transcription activation by E2F1

“…Rather, the results would suggest that the initial Myc interaction creates a state that facilitates the subsequent E2F1 interaction, possibly through a chromatin modification process. As such, we have demonstrated through ChIP assays that knockdown of Myc expression reduced acetylation on histone H4, consistent with previous work demonstrating a role for Myc in affecting H4 acetylation (Frank et al, 2001).…”

“…We propose that the requirement of Myc for activation of E2F genes may be to provide a 'licensing event', to ensure that the E2F genes are only activated when Myc activity has previously accumulated. Consistent with this speculation, recent studies have also indicated that Myc may act as a 'permissive' factor to allow other signals to activate target promoters (Frank et al, 2001). By so doing in the context of E2F gene promoter regulation and cell-cycle progression, cells would then only enter S phase when all of the necessary components for cell growth, encoded by the other myriad of genes regulated by Myc, have properly accumulated.…”

“…Recent work has provided evidence that Myc may control transcription via recruitment of a variety of proteins including histone acetyltransferases to control histone acetylation (Eisenman, 2001). In particular, chromatin IP assays have shown that Myc interaction mediates acetylation of histone H4 associated with gene activation (Frank et al, 2001). Given these results, and the role of Myc in facilitating E2F1 promoter Renilla and increasing amounts of HA-E2F1 activator DNA.…”

“…It's been estimated that Myc has a strong binding affinity to no less than 11% of promoters within the human genome (Fernandez et al, 2003). Although many genome-wide studies have focused on identifying gene promoters bound by Myc, more recent work has shown that Myc alone is not sufficient to induce expression of most target genes (Frank et al, 2001;Fernandez et al, 2003).…”

Deregulated expression of a novel component of TFTC/STAGA histone acetyltransferase complexes, rat SGF29, in hepatocellular carcinoma: possible implication for the oncogenic potential of c-Myc

“…rMTA1 and rODC promoters possess 10 and four E-boxes, respectively (Figure 6a). In growing K2 cells, c-Myc, rSGF29 and acetylated histone H3 were detected in the promoter regions, whereas in the E-boxless promoter of rat acetylcholine receptor (ACHR) gene (Frank et al, 2001), these proteins were hardly detected ( Figure 6b). In quiescent K2 cells the binding levels of these proteins were reduced.…”