Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide maps of chromatin state in K-RasLSL-G12D and K-RasLSL-G12D;Mll4fl/fl induced lung tumors in mice

ABSTRACT: Here, we show that the histone H3 lysine (H3K4) methyltransferase MLL4 (a COMPASS/SET1-like enzyme; also called KMT2D) is ranked the most highly inactivated epigenetic modifier in NSCLC tumors lung-specific loss of Mll4 accelerates K-RasG12D-induced lung tumorigenesis in mice while reducing their survival time. Mll4 loss upregulated tumor-promoting programs, such as glycolysis, which is also enriched in human lung tumors with low MLL4 levels or MLL4 inactivation. The inhibition of glycolysis selectively impeded the proliferation and tumorigenic growth of NSCLC cells bearing human MLL4-inactivating mutation. Mll4 loss caused widespread impairment of super-enhancer signals, including super-enhancer associated with the circadian transcriptional repressor gene Per2 which represses glycolysis genes in NSCLC cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE116659 | GEO | 2020/04/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Global gene expression profiling of K-RasLSL-G12D and K-RasLSL-G12D;Mll4fl/fl lung tumors using RNA sequencing

Project description:Here, we show that the histone H3 lysine (H3K4) methyltransferase MLL4 (a COMPASS/SET1-like enzyme; also called KMT2D) is ranked the most highly inactivated epigenetic modifier in NSCLC tumors lung-specific loss of Mll4 accelerates K-RasG12D-induced lung tumorigenesis in mice while reducing their survival time. Mll4 loss upregulated tumor-promoting programs, such as glycolysis, which is also enriched in human lung tumors with low MLL4 levels or MLL4 inactivation. The inhibition of glycolysis selectively impeded the proliferation and tumorigenic growth of NSCLC cells bearing human MLL4-inactivating mutation. Mll4 loss caused widespread impairment of super-enhancer signals, including super-enhancer associated with the circadian transcriptional repressor gene Per2 which represses glycolysis genes in NSCLC cells.

2020-04-13 | GSE116658 | GEO

Global gene expression profiling of shLUC (control) and shMLL4-1 and shMLL4-3 (MLL4-knockdown) LKR-10 mouse lung cancer cell using RNA sequencing

2020-04-13 | GSE143498 | GEO

MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis

Project description:Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes during cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors, as well as transcriptome and epigenome during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT). We show that MLL4 and CBP drive the dynamic enhancer epigenome, which correlates with the dynamic transcriptome. MLL3/MLL4 are required for CBP/p300 binding on enhancers activated during adipogenesis. Further, we show that MLL4 and CBP identify super-enhancers of adipogenesis and that MLL3/MLL4 are required for the formation of super-enhancers. Finally, in brown adipocytes differentiated in culture, MLL4 identifies primed super-enhancers of genes fully activated in BAT such as the thermogenic Ucp1. Comparison of MLL4-defined super-enhancers in brown and white adipogenesis predicted a list of brown-specific super-enhancers SEs associated genes that are likely to be important to BAT functions. These results establish MLL3/MLL4 and CBP/p300 as master enhancer epigenomic writers and suggest that enhancer-priming by MLL3/MLL4 followed by enhancer-activation by CBP/p300 sequentially shape dynamic enhancer landscapes during cell differentiation. Our data also provide a rich resource for understanding epigenomic regulation of brown adipogenesis.

2017-01-01 | GSE74189 | GEO

MLL4 establishes super-enhancers and broad H3K4me3 for tumor-suppressive function

Project description:Clusters of enhancers called super-enhancers are associated with gene activation. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines actively transcribed tumor suppressor genes. However, how these epigenetic signatures are regulated for tumor suppression is poorly understood. Here, we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (aka KMT2D) in mice spontaneously induces cerebellar tumors in brain while indirectly increasing expression of oncogenic programs, such as Ras activators and Notch pathway components. Mll4 loss caused widespread impairment of super-enhancers and broad H3K4me3. Notably, Mll4 loss reduced super-enhancer and broad H3K4me3 signals in tumor suppressor genes co-marked by both signatures, including Dnmt3a and Bcl6. MLL4 upregulates DNMT3A-mediated DNA methylation to downregulate expression of Ras activators and increases Bcl6 expression to suppress the Notch pathway. These findings suggest an unanticipated epigenetic tumor-suppressive mechanism in which MLL4 is required for establishing super-enhancers and broad H3K4me3 for anti-tumor programs in normal cells.

2018-11-13 | GSE95626 | GEO

Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Project description:Transcriptional enhancers instruct spatiotemporal gene expression and their dysfunction has long been known as one of the primary mechanisms that drive tumorigenesis and confer malignant tumor cell behaviors. However, it is largely unknown about whether tumor cell enhancer regulation plays a role in tumor immune evasion and anti-tumor immune response. Here, we demonstrate that tumor cell deletion of Mll3 and Mll4, two members of COMPASS family for enhancer H3K4 mono-methylation, increases tumor cell immunogenicity and promotes anti-tumor immune response. Loss of Mll4 potentiates therapeutic response to anti-Pd1 blockade in the murine melanoma model. Mechanistically, Mll4 loss leads to the widespread decrease of epigenetic signatures at both typical and super-enhancers, including the super-enhancer for Ago2 subunit of RNA-induced silencing complex (RISC) and the enhancers for DNA methyltransferases Dnmt3a and Dnmt1. Downregulation of Ago2 expression leads to double-stranded RNA (dsRNAs) stress to elicit interferon response while decreased expression of Dnmt3a and Dnmt1 derepresses Gsdmd and inflammatory caspases to trigger Gsdmd-mediated pyroptosis in Mll4-deficient tumor cells. Notably, transcriptional induction of interferon signaling and Gsdmd-mediated tumor cell pyroptotic death is crucial for the increased anti-tumor immunity and the improved immunotherapeutic efficacy in Mll4-deficient tumors. These findings reveal an important immune regulatory role of tumor cell enhancer regulation and provide molecular insights into the immunotherapeutic vulnerabilities of tumors bearing MLL3/MLL4 deficiency or loss of function mutations.

2022-10-05 | GSE192714 | GEO

The MLL3/MLL4 branch of the COMPASS family regulates H3K4 monomethylation at enhancers

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

Gene expression profiles of spontaneous metastasis in a K-ras/p53 mutant mouse model

2009-04-15 | GSE14449 | GEO

Gene expression profiles of spontaneous metastasis in a K-ras/p53 mutant mouse model

Project description:The biologic basis for NSCLC metastasis is not well understood. Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature. Primary lung adenocarcinomas and metastases from p53R172H∆g/+ K-rasLA1/+ mice or syngeneic tumors were isolated, carefully dissected to remove the adjacent tissue, snap-frozen in liquid nitrogen and stored at -80° until use. Part of each dissected tumor was histologically evaluated by a board-certified pathologist. Synthesis of cRNA and hybridization to Mouse Expression Array 430A 2.0 chips were performed. Two-sided t-paired tests using log-transformed expression values determined significant differences between primary tumors and metastasis.

2009-04-14 | E-GEOD-14449 | biostudies-arrayexpress

A UTX–MLL4–p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription (RNA-Seq)

Project description:Enhancer activation is a critical step for gene activation. Here we report a novel epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of naïve (unmarked) enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an “active enhancer landscape” and defines a mechanism for the joint deposition of H3K4me1 and H3K27ac.

2017-07-06 | GSE97702 | GEO

A UTX–MLL4–p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription (ChIP-Seq)

2017-07-06 | GSE97701 | GEO