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Genome binding/occupancy profiling of ccRCC cell line upon SETD2 rescue [ChIPseq_JHRCC12]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146539 | GEO | 2021/11/15

REPOSITORIES: GEO

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Chromatin landscape analysis of murine renal tubular epithelial cells upon SETD2 knockout [ATACseq_RTE]

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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