Lineage factor functions in renal carcinoma - ATAC-seq
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA686367 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Lineage factor functions in renal carcinoma
| PRJNA684309 | ENA
Project description:Lineage factor functions in renal carcinoma [I]
| PRJNA683897 | ENA
Project description:Lineage factor functions in renal carcinoma [II]
| PRJNA684310 | ENA
Project description:Lineage factor functions in renal carcinoma - ChIP-seq
| PRJNA686373 | ENA
Project description:The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.
2022-03-11 | GSE163485 | GEO
Project description:The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.
2022-03-11 | GSE163000 | GEO
Project description:The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.
2022-03-11 | GSE162948 | GEO
Project description:The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.
2022-03-11 | GSE163487 | GEO
Project description:Transcriptional lineage factors are a prominent class of essential genes in cancer, but the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether lineage factor pathways could be broadly exploited for cancer therapy remain poorly understood. Here, we have used clear cell renal cell carcinoma (ccRCC) as a model to characterise the mechanisms that underlie lineage factor dependence in cancer. Through CRISPR/Cas9 loss-of-function screening and functional validation we find that loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex, can confer an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. PAX8 inhibition resistant cells formed tumours with a dramatically altered histology showing neuroendocrine differentiation. Based on ATAC-seq and RNA-seq analysis, SMARCB1 inactivation leads to large-scale loss of kidney-specific epigenetic programmes, acquisition of a cellular state resembling that of rhabdoid tumours, and eventual activation of proliferative pathways. We show that these pathways are supported by the adoption of new transcriptional dependencies on IRF2, BHLHE40, and ZNFX1, factors that represent rare essential genes across different lineage-specific and oncogenic pathways, a principle validated in a large-scale CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. Thus, lineage factor requirements in cancer can switch upon challenge. The rules governing such lineage switching should be considered when designing novel lineage factor-targeted cancer therapies.
2023-07-19 | GSE183353 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-11 | GSE163001 | GEO