Next Generation Sequencing Facilitates Quantitative Analysis of MYC+ and MYC+; SETD2-/- Renal Tubular Cells Transcriptomes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE125381 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
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Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
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Project description:To explore potential role of SETD2 in PKD-ccRCC transition in vivo, we generated a PKD mouse model by overexpressing oncogene c-MYC under the control of the Ksp promoter (KM mice), and knockout Setd2 gene using the same Ksp promoter in this PKD mice (KMs mice) to establish a ccRCC mouse model. To further characterize biological responses trigered by SETD2 deletion during PKD-ccRCC transition at the mRNA level, we next conducted global transcriptomics studies.
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Project description:To explore a possible role of SETD2 in kidney development and tumorigenesis in vivo, we generated Setd2-floxed mice and deleted the Setd2 gene in tubular epithelial cells using a transgenic Ksp1.3/Cre mouse line. Then, we established our own c-MYC-transgene mouse line by overexpressing the human c-MYC under the control of the Ksp promoter to generate kidney disease mouse model. To get an insight into the mechanism of how SETD2 ablation promotes ccRCC formation in a c-MYC-generated PKD model, we performed RNA-seq using the renal tubules isolated from Wild Type, Setd2-KO, MYC-OE and MYC-OE; Setd2-KO mice.
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Project description:Next Generation Sequencing Facilitates Quantitative Analysis of MYC+ and MYC+; SETD2-/- Renal Tubular Cells Transcriptomes
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Project description:Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain–containing 2 (SETD2) has been identified as an important tumor suppressor gene in ccRCC. However, the role of SETD2 in tumorigenesis during the transition from PKD to ccRCC remains largely unexplored. Herein, we performed metabolomics, lipidomics, transcriptomics and proteomics with SETD2 loss induced PKD-ccRCC transition mouse model. To characterize biological responses triggered by SETD2 deletion during PKD-ccRCC transition at the protein level, we conducted global proteomics studies.
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Project description:Transcriptional profiling of human WT-PTECs, SETD2-KD PTECs, PBRM1-KD PTECs, and 10 different ccRCC derived cell lines. ccRCC derived cell lines showed distict expression signatures as compared to PTECs, some of them also present in SETD2-KD PTECs, and/or PBRM1-KD PTECs.
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Project description:Clear cell renal cell carcinomas (ccRCCs) harbor frequent mutations in epigenetic modifiers including SETD2, the writer for H3K36me3. We profiles DNA methylation across cell line models of SETD2 inactivation and SETD2 mutated primary tumors as this epigenetic mark is linked to H3K36me3 and is a targetable mark for cancer therapy. SETD2 depleted cell line models (long-term and acute) exhibited a hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across intergenic regions adjacent to low expression genes that became upregulated with dysregulation of the epigenome. Poised enhancers of developmental genes demonstrated enrichment for the hypermethylation phenotype. Deregulation of the epigenome observed in the cell line models was recapitulated in SETD2 mutated primary ccRCC, papillary renal cell carcinomas, and lung adenocarcinomas.
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Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
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Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
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