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Published on: October 28, 2014
WDR5 is a conserved regulator of protein synthesis gene expression
Audra F Bryan1, Jing Wang2, Gregory C Howard1
1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
Abstract:
WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the 'WIN' site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks-if any-that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.
Insights
WD repeat domain 5 (WDR5) protein regulates protein synthesis genes (PSGs) by binding to chromatin. Inhibiting WDR5
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- WDR5 is a conserved nuclear protein with crucial scaffolding functions in chromatin.
- WDR5 is a validated pharmacological target in cancer, with WIN site inhibitors showing anti-cancer activity.
- Understanding WDR5's nuclear functions and gene regulatory networks is essential for cancer therapy.
Purpose of the Study:
- To identify conserved WDR5 chromatin binding sites and regulated genes across cancer cell lines.
- To elucidate the role of the WIN site in WDR5 chromatin association.
- To determine if protein synthesis genes (PSGs) are direct targets of WDR5 and WIN site inhibitors.
Main Methods:
- Comparative genomic analyses of WDR5 chromatin binding.
- Chromatin immunoprecipitation (ChIP) assays.
- Functional assays to assess PSG regulation and inhibitor efficacy.
Main Results:
- Identified a conserved cohort of protein synthesis genes (PSGs) invariantly bound by WDR5.
- Demonstrated that the WIN site is critical for anchoring WDR5 to chromatin at PSG loci.
- Confirmed PSGs as direct, acute, and persistent targets of WIN site blockade in cancer cells.
Conclusions:
- WDR5 plays a significant transcriptional role in regulating biomass accumulation.
- WIN site inhibitors effectively repress gene networks controlling protein synthesis homeostasis.
- These findings support WDR5 and WIN site inhibitors as key players in cancer therapeutic strategies.
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