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Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation

ABSTRACT: Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation

PROVIDER: PRJNA1044050 | ENA |

REPOSITORIES: ENA

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Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [RNA-seq]

Project description:The histone methyltransferase KMT2D (alias MLL4) is frequently mutated in medulloblastoma (MB). Heterozygous loss of KMT2D is prevalent in MB. However, the role of heterozygous KMT2D loss remains unknown. Here, we show that heterozygous Kmt2d loss highly promotes Ptch+/–-driven MB genesis in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation (OXPHOS), in Ptch+/–-driven MB genesis. Heterozygous Kmt2d loss extensively diminished enhancer signals and H3K4me3 signature, including those for transcription-repressive tumor suppressor genes (e.g., Ncor2). NCOR2 repressed the expression of tumor-promoting genes. Combinatory pharmacological inhibition of OXPHOS and the enhancer-decommissioning demethylase LSD1 drastically reduced the tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss.

2025-06-02 | GSE293811 | GEO

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [ChIP-Seq]

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Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [CUT&RUN]

2025-06-02 | GSE248456 | GEO

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [RNA-seq]

Project description:Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [RNA-seq]

| PRJNA1246494 | ENA

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [CUT&RUN]

| PRJNA1044057 | ENA

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation [ChIP-Seq]

| PRJNA1044059 | ENA

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-06-02 | GSE248458 | GEO

H3K4me2 and gene expression profiling in control and KMT2D KD murine B220 cells

Project description:Define and compare H3K4me2 enrichment in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Compare gene expression by RNAseq in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Using H3K4me1/2 ChIPseq and RNAseq we profiled murine B220 purified cells from tumors transduced with EV (n=3) or KMT2D-shRNA (n=3).

2015-08-28 | E-GEOD-67291 | biostudies-arrayexpress

RNA-seq of KMT2D Knockout and KMT2D WT melanoma in mice

Project description:Somatic mutations in various epigenetic regulators, including histone methyltransferases KMT2C and KMT2D, have emerged as important cancer-driving events. However, the mechanism of action and therapeutic vulnerability imparted by these mutations remain poorly understood. We identified KMT2D and 8 other epigenetic regulators as potential suppressors to melanoma initiation through an in vivo pooled epigenome-focused RNAi screen. Loss of KMT2D, which exhibits somatic mutations in human melanoma and other cancers, drastically enhanced melanoma progression in xenograft models and a BRAFV600E-driven genetically engineered mouse model of melanoma. Epigenome profiling of 6 histone marks and chromatin state alterations showed substantial reprogramming of H3K4me1- and H3K27ac-marked active enhancer states in KMT2D mutant tumors. Energy metabolic pathways such as glycolysis, OxPhos and TCA/electron transport showed high degree of deregulation which was confirmed with metabolic profiling. Pharmacological abrogation of glycolysis led to reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, we find that enhancer loss at IGFBPs increases IGF signaling and downstream AKT phosphorylation that leads to upregulation of metabolic pathways rendering KMT2D mutant cells dependent on these energy metabolism pathways for their higher growth potential. Overall, we present evidence that KMT2D mutations promote tumorigenesis by reprogramming energy metabolism pathways through enhancer reprogramming.

2020-11-16 | GSE116852 | GEO

Analysis of transcriptome changes in Kmt2d deletion in cardiac mesoderm, anterior heart field precursors and cardiomyocytes

Project description:KMT2D is required in the cardiac mesoderm, anterior heart field precursors and cardiomyocytes. Kmt2d deletion in cardiac mesoderm (Mesp1Cre) is embryonic lethal at E10.5 and mutants have hypoplastic hearts; Kmt2d deletion in anterior heart field precursors (Mef2cAHF::Cre) deletion is embryonic lethal at E13.5 and mutants have defects in septation of outflow tract and interventricular septum (IVS); Kmt2d deletion in cardiomyocytes (Tnnt2::Cre) deletion is embryonic lethal at E14.5 and mutants have defects in IVS septation and compact myocardium. The goal of this study is to compare changes in gene expression in these Kmt2d conditional deletion mutants and understand common or distinct pathways dysregulated in absence of KMT2D. Whole genome gene expression analysis was performed on RNA isolated from control and mutant embryonic hearts (or right ventricles and outflow tract for anterior heart field deletion samples). Libraries were prepared using Illumina TruSeq Paired-End Cluster Kit v3, and sequenced with the Illumina HiSeq 2500 system for pair-ended 100 base pairs (PE 100 bp).

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