Unannotated microprotein EMBOW switches WDR5 between epigenetic and mitotic roles during cell cycle
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ABSTRACT:
PROVIDER: PRJNA879743 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21535172_1.fastq.gz | Fastqsanger.gz | |||
| SRR21535172_2.fastq.gz | Fastqsanger.gz | |||
| SRR21535173_1.fastq.gz | Fastqsanger.gz | |||
| SRR21535173_2.fastq.gz | Fastqsanger.gz | |||
| SRR21535174_1.fastq.gz | Fastqsanger.gz |
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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: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:Background: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5—a critical MYC cofactor—regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. Results: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. Conclusions: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
2024-03-29 | GSE244899 | GEO
Project description:Background: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5—a critical MYC cofactor—regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. Results: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. Conclusions: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
2024-03-29 | GSE244835 | GEO
Project description:Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus
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Project description:Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus
| PRJNA1024983 | ENA
Project description:Recent analysis of the human proteome via proteogenomics and ribosome profiling of the transcriptome revealed the existence of thousands of previously unannotated microprotein-coding small open reading frames (smORFs). Most functional microproteins were chosen for characterization because of their evolutionary conservation. However, one example of a non-conserved immunomodulatory microprotein in mice suggests that strict sequence conservation misses some intriguing microproteins. Here, we examine the ability of gene regulation to identify human microproteins with potential roles in inflammation or fibrosis of the intestine. To do this, we collected ribosome profiling data of intestinal cell lines and peripheral blood mononuclear cells (PBMCs), and then used gene expression of microprotein-encoding transcripts to identify strongly regulated microproteins, including several examples of microproteins that are only conserved with primates. This approach reveals a number of new microproteins worthy of additional functional characterization, and provides a dataset that can be queried in different ways to find additional gut microproteins of interest.
2024-10-23 | GSE269372 | GEO
Project description:Recent analysis of the human proteome via proteogenomics and ribosome profiling of the transcriptome revealed the existence of thousands of previously unannotated microprotein-coding small open reading frames (smORFs). Most functional microproteins were chosen for characterization because of their evolutionary conservation. However, one example of a non-conserved immunomodulatory microprotein in mice suggests that strict sequence conservation misses some intriguing microproteins. Here, we examine the ability of gene regulation to identify human microproteins with potential roles in inflammation or fibrosis of the intestine. To do this, we collected ribosome profiling data of intestinal cell lines and peripheral blood mononuclear cells (PBMCs), and then used gene expression of microprotein-encoding transcripts to identify strongly regulated microproteins, including several examples of microproteins that are only conserved with primates. This approach reveals a number of new microproteins worthy of additional functional characterization, and provides a dataset that can be queried in different ways to find additional gut microproteins of interest.
2024-10-23 | GSE269370 | GEO
Project description:Recent analysis of the human proteome via proteogenomics and ribosome profiling of the transcriptome revealed the existence of thousands of previously unannotated microprotein-coding small open reading frames (smORFs). Most functional microproteins were chosen for characterization because of their evolutionary conservation. However, one example of a non-conserved immunomodulatory microprotein in mice suggests that strict sequence conservation misses some intriguing microproteins. Here, we examine the ability of gene regulation to identify human microproteins with potential roles in inflammation or fibrosis of the intestine. To do this, we collected ribosome profiling data of intestinal cell lines and peripheral blood mononuclear cells (PBMCs), and then used gene expression of microprotein-encoding transcripts to identify strongly regulated microproteins, including several examples of microproteins that are only conserved with primates. This approach reveals a number of new microproteins worthy of additional functional characterization, and provides a dataset that can be queried in different ways to find additional gut microproteins of interest.
2024-10-23 | GSE269371 | GEO