Abstract 4994: Understanding the MYC and WDR5 interaction at chromatin
Authors: Alissa D. Guarnaccia, April M. Weissmiller, Lance R. Thomas, William P. Tansey
Journal: Cancer Research (2017)

Abstract MYC is an oncoprotein that is overexpressed in the majority of malignancies and contributes to an estimated 70,000-100,000 cancer deaths in the United States every year. The broad pro-tumorigenic functions of MYC stem from its role as a sequence-specific transcriptional regulator, controlling the expression of thousands of genes linked to cell cycle control, growth, and metabolism. Key to understanding how MYC causes cancer, therefore, is understanding the mechanisms through which it selects its target genes. Histone modifications, DNA sequence, and interactions with other transcription factors have all been suggested to influence where MYC binds chromatin, but a consistent signature has not been defined. Our laboratory recently discovered that the chromatin regulatory protein WDR5—a core component of histone modifying complexes—interacts directly with MYC and co-localizes with MYC at a majority of its target genes in human cells (Thomas et al., Mol. Cell, 58: 440-452, 2015). Point mutations in MYC that disable interaction with WDR5 do not impact the ability of MYC to bind naked DNA, but they do prevent MYC from recognizing target genes in the context of chromatin and from driving tumorigenesis in mice. These studies led us to propose that the MYC-WDR5 interaction is a critical determinant in MYC target gene recognition, in a process we refer to as “facilitated recruitment.” In the facilitated recruitment model, the presence of WDR5 at chromatin promotes MYC binding at certain genomic loci over others. The role of WDR5 in target gene selection by MYC can explain much of the plasticity in genome-wide binding patterns of MYC that have been reported, and may provide a new avenue for therapeutically targeting MYC in cancer. Two important questions are raised by these studies, however. How does WDR5 recognize and select its target genes? And what other functions, if any, does WDR5 play in regulating MYC target genes? To answer these questions, we are employing traditional and quantitative proteomics, together with biochemical approaches, to characterize the composition and stoichiometry of the WDR5-containing complex that associates with MYC. These studies, still ongoing, have demonstrated that this complex is devoid of canonical WDR5-interaction partners such as RBBP5 and HCF-1, revealing that the function of WDR5 in this setting is distinct from its well-characterized roles in histone modifications. We propose that the WDR5 complex that associates with MYC on chromatin is either entirely novel, or is a ‘ghost’ complex in which select protein components have been excluded by the direct interaction of MYC with WDR5. We continue to define the biochemical constituents of the MYC-WDR5 complex, and will interrogate their role in facilitated recruitment using a combination of genetic, biochemical, and genomic, approaches. Citation Format: Alissa D. Guarnaccia, April M. Weissmiller, Lance R. Thomas, William P. Tansey. Understanding the MYC and WDR5 interaction at chromatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2017-4994