Effect of Mll3 deletion in MCF7 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171445 | GEO | 2022/10/08
REPOSITORIES: GEO
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Project description:MLL3 inactivation mutations occurs frequently in human breast cancer. To understand the function of MLL3 inactivation, we compared the gene expression profiles of the vector control (WT) and Mll3-null mouse mammary stem cells generated by CRISPR. Affymetrix mouse Gene 2.0ST ships were used for microarray.
2016-09-19 | GSE79946 | GEO
Project description:Effect of Mll3 deletion in MCF7 cells
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Project description:To determine the effect of Mll3 deletion on H3K4me3 Chip signals in intestinal stem cell populations. This data has been described in the following article : Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin. Boles MK et al PLoS Genet. 2009 Dec;5(12) and its further analysis can be freely submitted for publication. For information on the proper use of data shared by the Wellcome Trust Sanger Institute (including information on acknowledgement), please see http://www.sanger.ac.uk/datasharing/ Abstract: Briefly we wanted to determine the effect of Mll3 deletion on H3K4me3 binding in cells of the intestine and to compare these to the H3K4me3 pattern found in wildtype animals.
2011-12-15 | E-ERAD-42 | biostudies-arrayexpress
Project description:Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of specific tumor suppressors on 7q remains elusive. Using RNAi and CRISPR/Cas9 approaches, we show that a ~50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3 suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor, and suggests a therapeutic option for this aggressive disease. Total RNA obtained from sorted lin-ckit+ hematopoietic stem and progenitor cells of recipient mice transplanted with shRen;p53-/- or shMll3;p53-/- cells at 6 weeks after transplant
2014-03-19 | E-GEOD-54313 | 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.
2023-06-01 | GSE200120 | GEO
Project description:Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of specific tumor suppressors on 7q remains elusive. Using RNAi and CRISPR/Cas9 approaches, we show that a ~50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3 suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor, and suggests a therapeutic option for this aggressive disease.
2014-03-19 | GSE54313 | GEO
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.
2021-04-14 | GSE160253 | GEO
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.
2021-04-14 | GSE160164 | 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:Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity.
2022-10-07 | GSE206658 | GEO