Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53035 | GEO | 2014/02/12
SECONDARY ACCESSION(S): PRJNA230709
REPOSITORIES: GEO
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Project description:Here we delineate the roles of RNA binding for WDR5 function on chromatin state and murine embryonic stem cell (ESC) maintenance. Examination of global transcriptional changes and mapping genome-wide transcription factors occupancy at distinct time points during the transdifferentiation process
2014-02-12 | E-GEOD-53035 | biostudies-arrayexpress
Project description:The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001.
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Project description:The Nucleosome Remodeling and Deacetylase (NuRD) complex is a chromatin regulatory complex that functions as a transcriptional co-repressor in metazoans. The NuRD subunit Mbd3 is essential for targeting and assembly of a functional NuRD complex as well as embryonic stem cell (ESC) pluripotency. Three Mbd3 isoforms (Mbd3a, Mbd3b, and Mbd3c) are expressed in mouse. Here, we find that the Mbd3c isoform contains a unique 50–amino acid N-terminal region that is necessary for Mbd3c to specifically interact with the histone H3 binding protein Wdr5. Domain analyses of Wdr5 reveal that the Wdr5 H3K4/MLL binding pocket is required for interaction with Mbd3c. We find that while Mbd3c KO ESCs differentiate normally, Mbd3c is redundant with the Mbd3a and Mbd3b isoforms in regulation of gene expression and ESC pluripotency, with the unique Mbd3c N-terminus required for this redundancy. Together, our data characterize a novel NuRD complex variant that functions specifically in ESCs
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Project description:WDR5 (WD repeat domain 5) plays an important role in the epigenetic regulation of gene transcription, involing in regulation of embryonic stem cell and cancer cell.Bladder cancer is one of the most common cancers that cause approximately 150,000 deaths per year worldwide.The goal of this study is to identify the target genes of WDR5 in bladder cancer.Our results inditcate that the genes regulated by WDR5 involved in a variety of biological functions, such as proliferation and anti-apoptosis. Bladder cancer cell line UM-UC-3 was transfected with the contol siRNA or two different WDR5 siRNA for 48h. The RNA of the transfected cells was extracted and hybridized on Affymetrix microarrays. We indentified the putative target genes of WDR5 in both WDR5 siRNA by comparing the diferent expressed genes among control, si-WDR5-2 and si-WDR5-3. We futher validated the data of microarray in UM-UC-3 and T24 by RT-qPCR and Western bloting.
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Project description:Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target genes activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P and this interaction facilitates the recruitment of the SET1/MLL complex and subsequent H3K4 trimethylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a six-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knock-down or chemical inhibition severely blocks WDR5 association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation, and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and a major driver of androgen-dependent prostate cancer cell proliferation. Identification of Histone 3 threonine 11 phosphorylation (H3T11P) marks and WDR5 binding sites in LNCaP cells treated with R1881 ligand (androgen) or solvent control.
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Project description:The oncoprotein transcription factor MYC is overexpressed in the majority of human cancers. Key to its oncogenic activity is the ability of MYC to bind chromatin and regulate broad gene expression patterns that drive and maintain the tumorigenic state. The interaction of MYC with chromatin is absolutely dependent on interaction with MAX, but may also be facilitated by additional chromatin-resident proteins such as WDR5. If the role of these additional proteins can be understood, they could serve as novel focal points for therapeutically targeting MYC. To stringently challenge the role of WDR5 in MYC function, we developed a Burkitt's Lymphoma system that allows inducible and quantitative exchange of wild-type for mutant forms of MYC defective for interaction with WDR5 or MAX. Using this system, we show that WDR5 recruits MYC to a small cohort of genes, enriched in those encoding ribosome protein subunits, and demonstrate that disrupting the MYC-WDR5 interaction is as effective as disrupting interaction with MAX at preventing tumor initiation and promoting tumor regression in vivo. These findings show that WDR5 is connected to a central tumorigenic function of MYC and forecast that small molecule WDR5 inhibitors could be broadly effective anti-cancer agents.
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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.
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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.
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