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WIN site inhibition disrupts a subset of WDR5 function

ABSTRACT: WIN site inhibition disrupts a subset of WDR5 function

PROVIDER: PRJNA761980 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15830001_1.fastq.gz	Fastqsanger.gz
	SRR15830001_2.fastq.gz	Fastqsanger.gz
	SRR15830003_1.fastq.gz	Fastqsanger.gz
	SRR15830003_2.fastq.gz	Fastqsanger.gz
	SRR15830005_1.fastq.gz	Fastqsanger.gz

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WIN site inhibition disrupts a subset of WDR5 function

Project description:This study demonstrates the impact of WIN site inhibitors versus WDR5 degradation on H3K4me and transcriptional processes in human Burkitt's lymphoma cells. We use RNA-seq to measure global transcript levels, ChIP-seq to map genomic H3K4me3, and PRO-seq to map genomic polymerase density and primary transcripts. Our data show that WIN site inhibition disables only a specific subset of WDR5 activity, and that H3K4me changes induced by WDR5 depletion do not explain accompanying transcriptional responses.

2022-02-03 | GSE183781 | GEO

The WDR5 WIN site interactome

Project description:The WIN site of WDR5 is a druggable pocket that is crucial for WDR5 protein function and carries therapeutic potential for treating cancer. This study evaluates the protein interactions affected by small molecule blockade of the WIN site of WDR5. We find that PDPK1 directly binds the WIN site of WDR5, and we investigate this newfound interaction through proteomic, biochemical, and genomic methods.

2021-01-19 | GSE150400 | GEO

The WDR5 WIN site interactome

Project description:The WDR5 WIN site interactome

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WIN site inhibition disrupts a subset of WDR5 function.

Project description:WDR5 nucleates the assembly of histone-modifying complexes and acts outside this context in a range of chromatin-centric processes. WDR5 is also a prominent target for pharmacological inhibition in cancer. Small-molecule degraders of WDR5 have been described, but most drug discovery efforts center on blocking the WIN site of WDR5, an arginine binding cavity that engages MLL/SET enzymes that deposit histone H3 lysine 4 methylation (H3K4me). Therapeutic application of WIN site inhibitors is complicated by the disparate functions of WDR5, but is generally guided by two assumptions-that WIN site inhibitors disable all functions of WDR5, and that changes in H3K4me drive the transcriptional response of cancer cells to WIN site blockade. Here, we test these assumptions by comparing the impact of WIN site inhibition versus WDR5 degradation on H3K4me and transcriptional processes. We show that WIN site inhibition disables only a specific subset of WDR5 activity, and that H3K4me changes induced by WDR5 depletion do not explain accompanying transcriptional responses. These data recast WIN site inhibitors as selective loss-of-function agents, contradict H3K4me as a relevant mechanism of action for WDR5 inhibitors, and indicate distinct clinical applications of WIN site inhibitors and WDR5 degraders.

| S-EPMC8813994 | biostudies-literature

WDR5 protein interactions at the WIN-site

Project description:The WIN site of WDR5 is a druggable pocket that impairs WDR5 protein function and carries therapeutic potential for treating cancer. This study evaluates the protein interactions affected by small molecule blockade of this surface on WDR5. Inhibited and uninhibited WDR5-containing complexes from HEK293 cells were quantitatively compared by SILAC-based proteomics. Of the high confidence proteins affected by this inhibition, one protein, PDPK1, was investigated further by mass spectrometry for identification of post translational modifications that could influence binding to WDR5.

2021-01-25 | PXD019209 | Pride

Displacement of WDR5 from chromatin by a pharmacological WIN site inhibitor with picomolar affinity

Project description:We discovered potent small molecule inhibitors against the WIN site of WDR5. These inhibitors selectively block the proliferation of mammalian cells carrying fusions of the MLL1 oncogene. Here, we show that these inhibitors result in the rapid displacement of WDR5 from chromatin in both sensitive (MV4:11) and non-sensitive (K562) cell lines, induce early changes in the distribution of active polymerases at a subset of WDR5-bound genes, and induce global transcript changes that are consistent with induction of the tumor suppressor p53.

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Proteome alterations in MLL-rearranged leukemia cells following WIN Site inhibition

Project description:WIN Site inhibitors bind the WIN Site of WDR5 resulting in decreased transcription of WDR5 target genes, many of which encode components of the protein synthesis machinery. In this study, we determined proteome alterations in an MLL-rearranged leukemia cell line treated for either 24 or 72 hours with a WIN Site inhibitor. The data from these studies, along with Ribo-Seq, RNA-Seq, and CRISPR screen experiments, guided us in assembling a collection of compounds that, when combined with WIN Site inhibitor, synergistically inhibit growth of MLL-rearranged leukemia cells.

2023-07-04 | PXD035129 | Pride

Multiomic characterization of WDR5 WIN site inhibition reveals actionable synergies for MLL-rearranged leukemia

Project description:In this study, we utilized a multi-omics approach to determine the transcriptional, translational, and proteomic responses to WIN Site inhibition in MLL-rearranged leukemia cells via RNA-Seq, Ribo-Seq, and quantitative proteomics, respectively. We also performed both a whole-genome targeting primary CRISPR screen and a secondary CRISPR screen targeting a currated collection of genes to determine genes important for sensitivity to WIN Site inhibition. These combined data sets rationally guided us in assembling a collection of compounds that, when combined with WIN Site inhibitor, synergistically inhibit growth of MLL-rearranged leukemia cells.

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Multiomic characterization of WDR5 WIN site inhibition reveals actionable synergies for MLL-rearranged leukemia

Project description:Multiomic characterization of WDR5 WIN site inhibition reveals actionable synergies for MLL-rearranged leukemia

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WDR5 is a conserved regulator of protein synthesis gene expression

Project description: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 both acute and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and reinforce the notion that WIN site inhibitors kill sensitive cancer cells by disrupting protein synthesis homeostasis.

2020-01-17 | GSE136451 | GEO

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