A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86855 | GEO | 2018/01/10
SECONDARY ACCESSION(S): PRJNA342781
REPOSITORIES: GEO
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Project description:Histone H3 lysine 4 trimethylation (H3K4me3) facilitates recruitment of transcription factors and epigenetic effectors to promote transcriptional activation and ensure cellular identity. This conserved histone mark is implemented by the COMPASS (COMplex of Proteins ASsociated with Set1) family of H3K4 methyltransferases. COMPASS members Set1A and Set1B have been accredited as primary depositors of global H3K4me3 in mammalian cells. Our previous studies in mouse embryonic stem cells (ESCs) demonstrated that deleting the enzymatic SET domain of Set1A does not perturb bulk H3K4me3, indicating possible compensatory roles played by other COMPASS methyltransferases. Here, we generated a series of ESC lines harboring compounding mutations of the COMPASS enzymes. We find that Set1B is functionally redundant to Set1A in implementing H3K4me3 at highly expressed genes, while Mll2 deposits H3K4me3 at less transcriptionally active promoters. Furthermore, Set1A and Set1B are responsible for broad H3K4me3 peaks, whereas Mll2 establishes H3K4me3 with narrow breadth. Most importantly, Mll2 helps preserve global H3K4me3 levels and peak breadth. Our results illustrate the biological flexibility of such enzymes in regulating transcription in a context-dependent manner to maintain stem cell identity, which could assist our understanding of their disease liability.
2020-06-27 | GSE152595 | GEO
Project description:Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations in the chromatin-modifying enzymes that regulate enhancer chromatin function across a wide range of human cancers. Defining the molecular mechanisms underlying the potential oncogenic function for these epigenetic mutations could serve as the basis for precision medicine approaches for cancer treatment. MLL4 (KMT2D) is a key histone lysine mono-methyltransferase within the COMplex of Proteins ASsociated with Set1 (COMPASS) family that regulates chromatin at enhancers, potentially functions as a tumor suppressor and is highly mutated in a large number of human cancers. We report that the mutations which cause MLL4 protein truncation also alter its subcellular localization, resulting in loss-of-function in the nucleus and gain-of-function in the cytoplasm. We demonstrate that isogenic correction of MLL4 truncation mutation rescues the aberrant localization phenotype and restores multiple MLL4 regulatory functions, including COMPASS integrity and stabilization, histone H3K4 mono-methylation, enhancer activation, and gene regulation. Moreover, isogenic correction diminishes the sensitivity of MLL4-mutated cancer cells to targeted metabolic inhibition. Using immunohistochemistry (IHC), we identified cytoplasmic MLL4 unique to the tissue of bladder cancer patients with MLL4 mutations. Using a preclinical carcinogen bladder cancer mouse model, we demonstrate that truncated, cytoplasmic MLL4 can be a biomarker for MLL4-mutated bladder cancers and predicts response to targeted metabolic inhibition therapy. We propose using the cytoplasmic MLL4 truncation phenotype as a prognostic marker in bladder cancer. We also highlight the broader potential for patient stratification based on MLL4 mutation status in MLL4 truncation diseases, including human cancers and Kabuki Syndrome.
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2018-11-14 | GSE122400 | 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. 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.
2013-09-30 | E-GEOD-51176 | biostudies-arrayexpress
Project description:Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalently marked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking at bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation. ChIP-Seq in mouse embryonic stem (mES) cells for MLL2. ChIP-seq of H3K4me1, H3K4me3 and H3K27me3 for mES cells with RNAi against MLL2(shMLL2) and control (shGFP). ChIP-seq of H3K4me3 in mES cells with RNAi against MLL3 (shMLL3). RNA-seq of mES cells with RNAi against MLL2 and control (shGFP). RNA-seq of control mES cells (shGFP) or MLL2 RNAi mES cells (shMLL2) induced with RA for 6h and 12h.
2013-08-11 | E-GEOD-48172 | biostudies-arrayexpress
Project description:Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Using co-immunopurification coupled to mass spectrometry-based proteomics, we characterized complex members and binding partners in various genetic contexts, using WDR-5 or CFP-1 proteins as baits.
2021-12-08 | PXD029904 | Pride
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
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Project description:The stimulation of trimethylation of histone H3 lysine 4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied with multiple mechanisms proposed for this form of histone crosstalk. Cps35/Swd2 within COMPASS is considered to bridge these processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation without interacting with Cps35/Swd2, and such crosstalk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we use biochemical, structural, in vivo, and ChIP-seq approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the crosstalk. Furthermore, the apparent wild-type levels of H3K4 trimethylation (H3K4me3) in the 762-Set1 strain is due to rogue methylase activity of this mutant resulting in the mislocalization of H3K4me3 from the promoter-proximal regions to gene bodies and intergenic regions. We have also performed detailed screens and identified yeast strains lacking H2Bub, but containing intact H2Bub enzymes, that have normal levels of H3K4me3, suggesting that ubiquitination may not directly stimulate COMPASS, but rather works in a context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the ubiquitination machinery and Cps35/Swd2 function to focus COMPASS’ H3K4me3 activity at promoter-proximal regions in a context dependent manner. ChIP-Seq for H3K4ME3 in S. cerevisie wild-type strains and strains expressing a truncated form of Set1: aa762-1080 Set1. H3K4ME3 ChIP-Seq was also compared for wild-type, leo1 knockout, and chd1 knockout strains
2014-01-09 | E-GEOD-53241 | biostudies-arrayexpress
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.
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