Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
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ABSTRACT:
PROVIDER: PRJNA761073 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15729234_1.fastq.gz | Fastqsanger.gz | |||
| SRR15729234_2.fastq.gz | Fastqsanger.gz | |||
| SRR15729235_1.fastq.gz | Fastqsanger.gz | |||
| SRR15729235_2.fastq.gz | Fastqsanger.gz | |||
| SRR15729236_1.fastq.gz | Fastqsanger.gz |
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Project description:Interplay between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 145 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex composition and function, and predict new functional interactions, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality.
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Project description:This work highlights the versatility of combining genetic screens with molecular profiling of cancer cells for high-throughput genetic interaction discovery that will not only offer critical insight into basic regulatory mechanisms of cancer epigenome progression, but also lead to new therapeutic targets for genetically defined and epigenetically perturbed cancers.
2023-06-09 | GSE183487 | GEO
Project description:Menin, the product of the MEN1 gene in humans (Men1 in mice), is responsible for the inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN1). menin interacts with the trithorax group (trxG) proteins (Drosophila) and the mixed-lineage leukemia (MLL) (humans) histone methyltransferase (HMTase) complex, and it alters histone tail modifications and the transcription of target genes. To explore a potential functional implication of menin in HCC, we stably transfected HepG2 or L-02 cells with either vectors or constructs expressing MEN1. A cDNA microarray analysis was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1. To obtain a broader understanding of the molecular network of menin in HCC, the whole genome microarray expression profiling was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1. Comparison of gene expression results from HepG2 or L-02 cells with either vectors or constructs expressing MEN1.
2015-07-07 | E-GEOD-70556 | biostudies-arrayexpress
Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and mouse Men1 null mouse embryonic fibroblast (MEF) cell lines. Tissues from KO mice were used to confirm and assess the findings from the MEN1 clinical samples and further explore the molecular mechanisms of global epigenetic changes following the inactivation of menin. We demonstrated that the inactivation of menin results in enhanced activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development. Global DNA methylation in tissues from patients with MEN1-parathyroid tumors. Thirty-eight human parathyroid specimens were used: 13 sporadic (non-MEN1) parathyroid adenomas, 12 MEN1-parathyroid tumors, 4 parathyroid carcinomas, and 9 normal parathyroids.
2015-12-22 | E-GEOD-64412 | biostudies-arrayexpress
Project description:Menin, the product of the MEN1 gene in humans (Men1 in mice), is responsible for the inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN1). menin interacts with the trithorax group (trxG) proteins (Drosophila) and the mixed-lineage leukemia (MLL) (humans) histone methyltransferase (HMTase) complex, and it alters histone tail modifications and the transcription of target genes. To explore a potential functional implication of menin in HCC, we stably transfected HepG2 or L-02 cells with either vectors or constructs expressing MEN1. A cDNA microarray analysis was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1. To obtain a broader understanding of the molecular network of menin in HCC, the whole genome microarray expression profiling was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1.
2015-07-07 | GSE70556 | GEO
Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and Men1 null mouse embryonic fibroblast (MEF) cell lines. We demonstrated that the inactivation of menin (the protein product of MEN1) results in increased activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development.
2015-12-22 | GSE64412 | GEO
Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.
2022-10-14 | PXD031928 | Pride
Project description:Multiple endocrine neoplasia type1 (MEN1), an inherited autosomal dominant syndrome characterized by the development of endocrine tumors including NETs, results from mutation in the MEN1 gene that encodes the protein menin. In mouse models, heterozygous loss of Men1 leads to multiple endocrine tumors with loss of heterozygocity at the Men1 locus. Men1 interacts with several partners to regulate cellular processes and gene expression through regulating histone modification. We used microarrays to detail the global gene expression change in Men1 knockout MEFs and identified up-regulated genes during this process.
2017-08-22 | GSE87733 | GEO
Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.
2020-07-01 | GSE144759 | GEO
Project description:The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML
| PRJNA733040 | ENA