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Genome-wide maps of chromatin state in KMT2D Knockout and KMT2D WT melanoma in mice

ABSTRACT: Genome-wide maps of chromatin state in KMT2D Knockout and KMT2D WT melanoma in mice

PROVIDER: PRJNA480444 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7504530.fastq.gz	Fastqsanger.gz
	SRR7504521.fastq.gz	Fastqsanger.gz
	SRR7504531.fastq.gz	Fastqsanger.gz
	SRR7504522.fastq.gz	Fastqsanger.gz
	SRR7504532.fastq.gz	Fastqsanger.gz

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Genome-wide maps of chromatin state in 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 | GSE116851 | GEO

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

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

Project description:RNA-seq of KMT2D Knockout and KMT2D WT melanoma in mice

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ChIP-seq and RNA-seq analysis of KMT2D-silenced metastatic melanoma cells

Project description:Purpose: Study of the mechanism trough which KTM2D regulates chromatin modification and transcription in a xenograft model of human metatstatic melanoma Methods: We generated patient derived xenografts (PDXs) from metastatic melanoma (MM) biopsies of three different patients. The MMs carry NRASQ61L, NRASQ61Q or BRAFV600 mutations. Cells from secondary PDX (PDX2) were transduced with lentiviral vectors carrying Luciferase (shLuc) and KMT2D (shKMT2D) hairpins and mRNA profiles and genome-wide chromatin-state maps were generated by deep sequencing using Illumina HiSeq2000. Results: we found that KMT2D regulates the activity of a subset of enhancers required for expression of specific genes.

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Genome-wide maps of chromatin state difference in KMT2D Knockdown/Control PC-3 Cells

Project description:KMT2D is a histone methyltransferase for catalyzing the monomethylation of H3K4. The H3K4me1 is prominent on active enhancers and participates in gene expression regulation. Loss of KMT2D in cancer has been approved to impact on a set of gene expression by the reduction of H3K4me1 level. To identify the direct target of KMT2D in prostate cancer, we performed H3K4me1 ChIP-seq with KMT2D knockdown and control PC-3 cells.

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Genome-wide maps of transcriptomic and epigenomic state in melanoma cell lines

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DBC1 is a positive regulator of enhancer epigenomic writers KMT2D and p300.

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Project description:A mechanistic relationship between tumor epigenetic plasticity and nongenetic adaptive resistance to therapy is described, with MAPK inhibition of BRAF-mutant melanoma cells providing the model system. Upon inhibition, these largely melanocytic cells undergo reversible cell-state changes, ultimately yielding a drug-resistant mesenchymal-like phenotype. Epigenomic and transcriptomic kinetic studies, coupled with information theory and dynamic system modeling, revealed that, after just 3-days of treatment, RelA drives chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. Specifically, RelA transcriptionally inhibits SOX10 and NFKBIE through recruiting KDM5B and HDAC1 to down-regulate histone marks H3K4me3 and H3K27ac at their promoter regions. Suppression of SOX10 mediates melanoma regression towards drug-refractory phenotypes. These findings were confirmed in melanoma patients under MAPK inhibitor treatment, providing mechanistic insights into resistance-leading epigenetic reprogramming triggered following drug exposure.

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Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRAS-mut melanoma

Project description:These data support our manuscript "Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRAS-mut melanoma". Proteomics was performed for M93-047 melanoma cells expressing vector control, S6K1 shRNA knockdown or S6K2 shRNA knockdown.

2019-02-25 | MSV000083480 | MassIVE

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