H3K4me2 and WDR5 enriched chromatin interacting lncRNAs
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB20225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1910942.fastq.gz | Fastqsanger.gz | |||
| ERR1910943.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:Coordinate loss of MLL1 and WDR5 occupancy caused by HOTTIP knockdown were observed in distal HOXA genes. These regions correspondingly lost H3K4me3 and H3K4me2, without changes in pan-histone or H3K27me3. human foreskin fibroblasts (CRL2091), anti-H3K4me3 (Abcam ab8580, lot#1016899), anti-H3K4me2 (Abcam ab32356, lot#947550), anti-H3K27me3 (Abcam ab4729, lot#1021724), anti-histone H3 (Abcam ab1791, lot#1025144), anti-MLL1 (gift of R. Roeder, Rockefeller University), and anti-WDR5 (gift of W. Herr, UNIL) Comparison of occupancy of MLL1 and WDR5 of siGFP and siHOTTIP foreskin fibroblasts on HOX tiling array. Human foreskin fibroblasts are transfected with siGFP or siHOTTIP for 72 hrs. The cells are harvesed and ChIP performed with H3K4me3, H4K27me3, H3K4me2, MLL1, WDR5, and histone antibodies.
2011-03-21 | E-GEOD-26540 | biostudies-arrayexpress
Project description:Coordinate loss of MLL1 and WDR5 occupancy caused by HOTTIP knockdown were observed in distal HOXA genes. These regions correspondingly lost H3K4me3 and H3K4me2, without changes in pan-histone or H3K27me3. human foreskin fibroblasts (CRL2091), anti-H3K4me3 (Abcam ab8580, lot#1016899), anti-H3K4me2 (Abcam ab32356, lot#947550), anti-H3K27me3 (Abcam ab4729, lot#1021724), anti-histone H3 (Abcam ab1791, lot#1025144), anti-MLL1 (gift of R. Roeder, Rockefeller University), and anti-WDR5 (gift of W. Herr, UNIL)
2011-03-21 | GSE26540 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and the well-established IMiDs:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling revealed that gene targets of WDR5 and IMiDs:CRBN were both repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a matched VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE195729 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE175547 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE175544 | 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.
2023-09-19 | PXD036699 | Pride
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
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:Recently lncRNAs have been implicated in the sub-compartmentalization of eukaryotic genome via genomic targeting of chromatin remodelers. To explore the function of lncRNAs in the maintenance of active chromatin, we characterized lncRNAs from the chromatin enriched with H3K4me2 and WDR5 using chromatin RNA immunoprecipitation (ChRIP). Significant portion of these enriched lncRNAs were arranged in antisense orientation with respect to their protein coding partners. Among these, 209 lncRNAs, commonly enriched in H3K4me2 and WDR5 chromatin fractions, were named as active chromatin associated lncRNAs (active lncCARs). Interestingly, 43% of these active lncCARs map to divergent transcription units. Divergent transcription (XH) units were overrepresented in the active lncCARs as compared to the inactive lncCARs. ChIP-seq analysis revealed that active XH transcription units are enriched with H3K4me2, H3K4me3 and WDR5. WDR5 depletion resulted in the loss of H3K4me3 but not H3K4me2 at the XH promoters. Active XH CARs interact with and recruit WDR5 to XH promoters, and their depletion leads to decrease in the expression of the corresponding protein coding genes and loss of H3K4me2, H3K4me3 and WDR5 at the active XH promoters. This study unravels a new facet of chromatin-based regulation at the divergent XH transcription units by this newly identified class of H3K4me2/WDR5 chromatin enriched lncRNAs.
| S-EPMC6182144 | biostudies-literature