Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts

Abstract

The transition from quiescence to proliferation is a key regulatory step that can be induced by serum stimulation in cultured fibroblasts. The transcription factor Myc is directly induced by serum mitogens and drives a secondary gene expression program that remains largely unknown. Using mRNA profiling, we identify close to 300 Myc-dependent serum response (MDSR) genes, which are induced by serum in a Myc-dependent manner in mouse fibroblasts. Mapping of genomic Myc-binding sites by ChIP-seq technology revealed that most MDSR genes were directly targeted by Myc, but represented a minor fraction (5.5%) of all Myc-bound promoters (which were 22.4% of all promoters). Other target loci were either induced by serum in a Myc-independent manner, were not significantly regulated or were negatively regulated. MDSR gene products were involved in a variety of processes, including nucleotide biosynthesis, ribosome biogenesis, DNA replication and RNA control. Of the 29 MDSR genes targeted by RNA interference, three showed a requirement for cell-cycle entry upon serum stimulation and 11 for long-term proliferation and/or survival. Hence, proper coordination of key regulatory and biosynthetic pathways following mitogenic stimulation relies upon the concerted regulation of multiple Myc-dependent genes.

Identification of MYC-Dependent Transcriptional Programs in Oncogene-Addicted Liver Tumors

“…S2G), suggesting equivalent proliferative activities. Both forms of MYC also rescued cell proliferation in mouse 3T9 fibroblasts upon deletion of the endogenous c-MYC gene (25), as shown by cell counting, BrdUrd incorporation, and colony formation ( Supplementary Fig. S3A-S3C), confirming that MYC-VD possesses an intact proliferative ability.…”

Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity

“…Expression of MYC target genes is dependent on MYC's dimerization with MAX (25) and subsequent binding to chromatin, mainly through the recognition of a DNA-binding motif (E-box) in a permissive chromatin context (23,24,26). Another key aspect affecting the function of MYC is its binding to transcriptional cofactors, which affects its activity as a transcriptional activator or repressor and its ability to bind to chromatin (27)(28)(29). MYC is targeted for rapid degradation under physiological conditions (30), and this process is tightly regulated by sequential posttranslational modifications, such as phosphorylation at the key residues, serine 62 (S62) and threonine 58 (T58) (31,32).…”

c-MYC partners with BPTF in human cancer

“…Real preal@cnio.es transcription. 6 In contrast, c-MYC-driven apoptosis is mostly indirect: it involves the inhibition of MIZ1 without direct binding of c-MYC to DNA and stabilization of the cyclin dependent kinase inhibitor p19ARF (CDKN2A, best known as p19ARF) and the tumor suppressor p53 (TP53, best known as p53). 5 Based on these findings, we propose that BPTF is only required for c-MYC functions that involve direct binding to chromatin (Fig.…”