2-hydroxyglutarate drives whole-genome hypermethylation in kidney cancer cells with inactivated VHL
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ABSTRACT:
PROVIDER: PRJNA637247 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11923142_1.fastq.gz | Fastqsanger.gz | |||
| SRR11923142_2.fastq.gz | Fastqsanger.gz | |||
| SRR11923143_1.fastq.gz | Fastqsanger.gz | |||
| SRR11923143_2.fastq.gz | Fastqsanger.gz | |||
| SRR11923144_1.fastq.gz | Fastqsanger.gz |
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Project description:Hypermethylation of tumor suppressors and other aberrations of DNA methylation in tumors play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions including hypoxia. The response to hypoxia is mainly achieved through activation of the transcription program associated with HIF1a transcription factor. VHL inactivation by genetic or epigenetic events, which also induces aberrant activation of HIF1a, is the most common driver event for renal cancer. With whole-genome bisulfite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We show that global genome hypermethylation in VHL mutants can be explained by the accumulation of 2-hydroxyglutarate -- a metabolite that inhibits DNA demethylation by Tet enzymes.
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Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.
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Project description:RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused accumulation of chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity. Combined Rassf1a and Vhl deletion in renal epithelial cells in vivo increased proliferation and caused mild tubular disorganization, but did not lead to the development of kidney tumors. Single cell RNA-sequencing unexpectedly revealed that Rassf1a deletion or Vhl deletion both induce the expression of an overlapping set of genes in a sub-population of proximal tubule cells. Many of these genes are also upregulated in the Vhl/Trp53/Rb1 deficient mouse model of ccRCC. In other subsets of proximal tubule cells, combined Vhl/Rassf1a deletion induced the expression of additional genes that were not upregulated in each of the single knockouts. The expression of the human homologues of Rassf1a-regulated genes correlate negatively with RASSF1 expression levels in human ccRCC, suggesting that the loss of RASSF1A function establishes a ccRCC-characteristic gene expression pattern.
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Project description:RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused accumulation of chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity. Combined Rassf1a and Vhl deletion in renal epithelial cells in vivo increased proliferation and caused mild tubular disorganization, but did not lead to the development of kidney tumors. Single cell RNA-sequencing unexpectedly revealed that Rassf1a deletion or Vhl deletion both induce the expression of an overlapping set of genes in a sub-population of proximal tubule cells. Many of these genes are also upregulated in the Vhl/Trp53/Rb1 deficient mouse model of ccRCC. In other subsets of proximal tubule cells, combined Vhl/Rassf1a deletion induced the expression of additional genes that were not upregulated in each of the single knockouts. The expression of the human homologues of Rassf1a-regulated genes correlate negatively with RASSF1 expression levels in human ccRCC, suggesting that the loss of RASSF1A function establishes a ccRCC-characteristic gene expression pattern.
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Project description:Vhl and Pbrm1 double deletion effect on kidney
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Project description:To unravel the potential cooperative roles of oxygen-regulated signaling pathways; von Hippel-Lindau (VHL) tumor suppressor protein and hypoxia-inducible factor (HIF) transcription factors, we have generated mutant mice with; Vhlh, Vhlh/Hif1α, Vhlh/Hif2α and Vhlh/Hif1α/Hif2α gene alleles floxed. Subsequently primary kidney cells were isolated, cultured and infected with Adenoviruses bearing either Cre/GFP or GFP expression only. Agilent cDNA microarrays were utilized to compare the gene expression profiles of the kidney epithelial cells from aforementioned cell cultures to gain insight about the molecules and signaling pathways that drive aberrant cellular proliferation in clear cell renal cell carcinoma (ccRCC). 24 independent biological samples from 4 genetic experimental conditions were hybridized in two- color format on 13 Mouse GE 4x44K v2 Microarray Kit (Design ID 026655) arrays. Eventual dye specific hybridization effects were controlled with dye swap on biological replicates. For an each experimental condition 3 arrays were use, except of one where 4 arrays were used (one sample combination in repetition with a dye swap). For the final analysis the gene expression levels were dye effect corrected and values for biological replicates were averaged to obtain a matrix with gene expression levels for 4 independent biological (1. Vhlh-/-, 2. Vhlh-/-/Hif1α-/-, 3. Vhlh-/-/Hif2α-/- and 4. Vhlh-/-/Hif1α-/-/Hif2α-/-) conditions.
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Project description:We are studying a tumor suppressor gene, von Hippel-Lindau (VHL). In humans, VHL mutations cause renal cell carcinoma of the clear cell type (ccRCC). We have generated a knockout mouse strain in which mouse Vhl is conditionally deleted in the kidney epithelium (that is, a subset of tubules including collecting ducts and ascending loop of Henle). Instead of ccRCC, these mice developed severe inflammation and fibrosis, accompanied by hyperplasia and the appearance of transformed clear cells. These phenotypes therefore support the notion that inflammation is the tissue precondition of cancer. Our hypothesis is that VHL loss-of-function-induced inflammation contribute to the initiation of carcinogenesis, through a mechanism that we want to determine. The aim of the microarray is to identify genes involved in the overgrowth of the epithelium, as well as in inflammation and fibrosis that may be important for ccRCC initiation.
2018-06-28 | GSE116326 | GEO
Project description:CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard of care agent, axitinib. RNAseq analysis was utilized to evaluate the expression profile produced by the targeted loss of Vhl, Pbrm1, Keap1 and Tsc1 in these mouse tumors. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2-independent.
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