CARM1-mediated methylation of ASXL2 impairs tumor suppressor gene activation by MLL3/COMPASS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA757091 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15569700.fastq.gz | Fastqsanger.gz | |||
| SRR15569800.fastq.gz | Fastqsanger.gz | |||
| SRR15569701.fastq.gz | Fastqsanger.gz | |||
| SRR15569801.fastq.gz | Fastqsanger.gz | |||
| SRR15569702.fastq.gz | Fastqsanger.gz |
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Project description:An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BAP1 deubiquitinase (DUB) complex negatively regulates Polycomb activity and also recruits the Trithorax histone H3K4 methyltransferase, MLL3/COMPASS, to the enhancers of tumor suppressor genes. We and others have demonstrated that the BAP1-MLL3 pathway is mutated in several differ cancers. Yet, how BAP1 recruits MLL3 to these loci remains a fundamentally important unanswered question. Here we demonstrate that ASXL2 directly mediates the interaction between the BAP1 complex and MLL3/COMPASS. ASXL2 loss abolishes the MLL3-BAP1 interaction, leading to decreased MLL3 occupancy at enhancers and reduced expression of BAP1-MLL3 target genes. The interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4, also known as CARM1), which methylates ASXL2 on R639/R641. Methylation of ASXL2 by CARM1 blocks binding to MLL3 binding and impairs the expression of MLL3 dependent genes. This finding uncovers a novel transcription repression function for CARM1 and provides a unique insight into the BAP1/ASXL2/MLL3 axis, which is controlled by arginine methylation and could serve as a target for potential cancer therapeutics.
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Project description:An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BRCA1 associated protein-1 (BAP1) deubiquitinase negatively regulates Polycomb activity and recruits the Trithorax histone H3K4 methyltransferase, mixed-lineage leukemia protein 3 (MLL3) within Complex Proteins Associated with Set1 (COMPASS), to the enhancers of tumor suppressor genes. We previously demonstrated that the BAP1-MLL3 pathway is mutated in several cancers, yet how BAP1 recruits MLL3 to its target loci remains an important unanswered question. We demonstrate that the ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS. ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. Interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4/CARM1), which methylates ASXL2 at R639/R641. ASXL2 methylation blocks binding to MLL3 and impairs the expression of MLL3/COMPASS-dependent genes. This previously unidentified transcriptional repressive function of CARM1 provides insight into the BAP1/MLL3-COMPASS axis and reveals a potential cancer therapeutic target.
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Project description:Histone H3 lysine 4 (H3K4) can be mono-, di-, and trimethylated by members of the COMPASS (COMplex of Proteins ASsociated with Set1) family from yeast to human and these modifications can be found at distinct regions of the genome. Monomethylation of histone H3K4 (H3K4me1) is relatively more enriched at metazoan enhancer regions compared to trimethylated histone H3K4 (H3K4me3), which are found at transcription start sites in all eukaryotes. Our recent studies in Drosophila demonstrated that the Trithorax-related (Trr) branch of the COMPASS family regulates enhancer activity and is responsible for the implementation of H3K4me1 at these regions. There are six COMPASS family members in mammals, two of which, MLL3 and MLL4, are most closely related to Drosophila Trr. Here, we use ChIP-seq of this class of COMPASS family members in both human HCT116 cells and mouse embryonic stem cells and find that MLL4 is preferentially found at enhancer regions. MLL3 and MLL4 are frequently mutated in cancer, and indeed, the widely used HCT116 cancer cell line contains inactivating mutations in the MLL3 gene. Using HCT116 cells in which MLL4 has also been knocked out, we demonstrate that MLL4 is a major regulator of H3K4me1 in these cells, with the greatest loss of monomethylation at enhancer regions. Moreover, we found a redundant role between Mll3 and Mll4 in enhancer H3K4 monomethylation in mouse embryonic fibroblast (MEF) cells. These findings suggest that mammalian MLL3/MLL4 function in the regulation of enhancer activity and enhancer-promoter communication during gene expression and that mutations of MLL3 and MLL4 found in cancer could exert their properties through enhancer malfunction. ChIP-Seq in mouse embryonic stem (mES) cells for MLL4. ChIP-seq of MLL4 and p300 in human parental HCT116 cells. ChIP-seq of H3K4me1, H3K4me2 and H3K4me3 in parental HCT116 cells and HCT116 cells with Mll4∆set.
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Project description:Epigenetic alterations due to abnormalities in the enzymatic machineries modifying chromatin, are frequently reported in developmental diseases and in a variety of human cancers. However, the cellular dependency and functional outcome of epigenetic alterations during these processes have not been fully elucidated. In this study, we depleted two of the most frequently mutated epigenetic factors, the MLL3 and MLL4 components of the COMPASS family, in mouse embryonic stem cells (mESCs) to investigate the cellular vulnerabilities when enhancer functions are compromised as the result of MLL3-4/COMPASS loss. CRISPR dropout screens revealed synthetic lethality of purine and pyrimidine nucleotide synthesis pathway suppression in cells with MLL3/4 loss. We observed a metabolic usage shift towards purine synthesis in Mll3/4 knockout mESCs. Subsequently, Mll3/4 KO cells exhibited enhanced sensitivity to purine synthesis inhibitor lometrexol, which induced unique gene expression signature changes in Mll3/4 KO cells. A tandem mass tag (TMT) proteomics profiling further identified upregulation of purine metabolism factors in Mll3/4KO cells. We also identified the top MLL3/4 target genes coinciding with suppression of the purine metabolism pathway. Finally, in vivo cancer studies show that tumors mutated for MLL3 and/or MLL4 are very sensitive to purine synthesis inhibitor lometrexol in culture and in animal models of cancer. Taken together, we depict a metabolic dependency map for cells deficient for epigenetic factors and provide insights into cancer treatments related to epigenetic alterations corresponding with MLL3/4 COMPASS malfunction.
2023-06-01 | GSE200120 | GEO
Project description:Histone H3 lysine 4 (H3K4) can be mono-, di-, and trimethylated by members of the COMPASS (COMplex of Proteins ASsociated with Set1) family from yeast to human and these modifications can be found at distinct regions of the genome. Monomethylation of histone H3K4 (H3K4me1) is relatively more enriched at metazoan enhancer regions compared to trimethylated histone H3K4 (H3K4me3), which are found at transcription start sites in all eukaryotes. Our recent studies in Drosophila demonstrated that the Trithorax-related (Trr) branch of the COMPASS family regulates enhancer activity and is responsible for the implementation of H3K4me1 at these regions. There are six COMPASS family members in mammals, two of which, MLL3 and MLL4, are most closely related to Drosophila Trr. Here, we use ChIP-seq of this class of COMPASS family members in both human HCT116 cells and mouse embryonic stem cells and find that MLL4 is preferentially found at enhancer regions. MLL3 and MLL4 are frequently mutated in cancer, and indeed, the widely used HCT116 cancer cell line contains inactivating mutations in the MLL3 gene. Using HCT116 cells in which MLL4 has also been knocked out, we demonstrate that MLL4 is a major regulator of H3K4me1 in these cells, with the greatest loss of monomethylation at enhancer regions. Moreover, we found a redundant role between Mll3 and Mll4 in enhancer H3K4 monomethylation in mouse embryonic fibroblast (MEF) cells. These findings suggest that mammalian MLL3/MLL4 function in the regulation of enhancer activity and enhancer-promoter communication during gene expression and that mutations of MLL3 and MLL4 found in cancer could exert their properties through enhancer malfunction.
2013-09-30 | GSE51176 | GEO
Project description:Catalytic-inactivating mutations within the Drosophila enhancer H3K4 monomethyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared to whole-gene deletions for these COMPASS members. To identify essential histone methylatransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ~80 amino acid UTX-Stabilization-Domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential non-catalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.
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Project description:The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers
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Project description:Mono-methylation of histone H3 on lysine 4 (H3K4me1) and acetylation of histone H3 on lysine 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and enhancers. Although in yeast all H3K4 methylation patterns including H3K4me1 are implemented by Set1/COMPASS, there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of mammalian Mll3/4, can function as a major H3K4 mono-methyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac in various tissues. Assays with the cut wing margin enhancer imply a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrates that Trr is required for H3K4me1 and H3K27ac on chromatin signatures that resemble the histone modification patterns described for enhancers. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 mono-methyltransferase Trr, and the H3K27 demethylase, UTX, cooperate to regulate the transition from inactive/poised to active enhancers. ChIP-seq of Trr, LPT, UTX in Drosophila S2 Cells. ChIP-seq of H3K4me1, H3K4me3, H3K27ac, H3K27me3 in WT and Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1, H3K27me3 in LPT knock-down Drosophila S2 cells. ChIP-seq of LPT and UTX in Trr knock-down Drosophila S2 cells. ChIP-seq of H3K4me1 and H3K27me3 in MLL1(+/+), MLL1(-/-), MLL3(+/+), and MLL3(-/-) Mouse Embryonic Fibroblasts (MEFs).
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