Effect of MLL3 deletion in mammary stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79946 | GEO | 2016/09/19
SECONDARY ACCESSION(S): PRJNA317474
REPOSITORIES: GEO
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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.
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Project description:MLL3 is a histone H3K4 methyltransferase which is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 knockout by CRISPR/sgRNA did not elevate proliferation rate of cancer cells, but significantly enhanced cell migration. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused down regulation of H3K4me1 and H3K27ac on an enhancer ~ 8 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter, and repression of enhancer with dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.
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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.
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