WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162968 | GEO | 2021/02/23
REPOSITORIES: GEO
Similar Datasets
Project description:WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.
| PRJNA684036 | ENA
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.
2014-07-01 | E-GEOD-55279 | biostudies-arrayexpress
Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.
2023-09-19 | PXD036699 | Pride
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.
2014-07-01 | GSE55279 | GEO
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
Project description:Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex for maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
2023-01-26 | GSE199110 | GEO
Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.
2023-09-07 | GSE213209 | GEO
Project description:Histone H3 Lys 4 methylation (H3K4me) is deposited by the conserved SET1/MLL methyltransferases acting in multiprotein complexes including Ash2 and Wdr5. While individual subunits contribute to complex activity, how they influence gene expression in a specific tissue remains largely unknown. In caenorhabditis elegans, SET-2/SET1, WDR-5.1 and ASH-2 are differentially required for germline H3K4 methylation. Using expression profiling on germlines from animals lacking set-2, ash-2 or wdr-5.1, we show that these subunits play unique and redundant functions to promote expression of germline genes and repress somatic genes. We further show that in set-2 and wdr-5.1 deficient germlines, somatic gene misexpression is associated with conversion of germ cells into somatic cells, and that nuclear RNAi acts in parallel with SET-2 and WDR-5.1 to maintain germline identity. These findings uncover a unique role for SET-2 and WDR-5.1 in preserving germline pluripotency, and underline the complexity of the cellular network regulating this process. Gene misregulation in SET1/set-2, wdr-5.1 and ash-2 defective germlines
2014-09-04 | E-GEOD-61094 | biostudies-arrayexpress
Project description:Active gene transcription requires accessible chromatin. Post-translational modifications of histone proteins modulate accessibility to target genes, a process that is controlled by multiple chromatin modifying enzymes, remodelers and epigenetic reader proteins. Histone H3K4 methylation serves as hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMTs). For proper function of HMT activity, several adaptor proteins are required. One of these proteins is the WD-repeat containing protein 5 (WDR5) that acts as scaffolding component in HMT complexes and that has been associated with controlling transcription factors including MYC and long non-coding RNAs. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types has made WDR5 an attractive cancer drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might be an elegant way to target all oncogenic function. In this study, we present the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds. We show that linker nature and length are essential for successful degradation and strongly influences the degradation rate. In the presented datasets, we determined the intracellular degradation specificity of the WDR5 PROTACs (8g, 6, 17b, 14). We therefore treated MV4-11 cells with 8g and 17b, the corresponding ligands 6 and 14, or DMSO and quantified the induced degradation using a label free approach.
2022-01-27 | PXD025257 | Pride