The connections between hypoxia pathway signaling and the development of cancer are nowhere more relevant than in renal cell carcinoma. Hypoxia, the reduction in oxygen content in tissues, leads to the stabilization of the transcription factors Hypoxia-inducible factor 1 (HIF1) and Hypoxia-inducible factor 2 (HIF2) which normally result in the transcriptional activation of a genetic program that results in transient metabolic adaptation. In human clear cell renal cell carcinoma (ccRCC), this pathway is co-opted by mutations in the Von Hippel Lindau gene (VHL), which normally mediates rapid proteosomal degradation of HIF under conditions of normal oxygen levels. Without VHL activity, HIF accumulates as under conditions of hypoxia, translocates to the nucleus and activates a transcriptional program. However, the HIF transcriptional program induced by hypoxia is not identical to the HIF transcriptional program associated with aberrant HIF expression. The mechanisms resulting in retargeting of these transcription factors are unknown. However, recently deep sequencing efforts have identified recurrent mutations in genes encoding epigenetic regulators, including chromatin remodeling complex members and enzymes that modify histones. The recurrent nature of these events suggests that they are relevant to cancer development, rather than bystander mutations. However, the role of these mutations in ccRCC remains unknown. We hypothesize that mutations of epigenetic regulators identified in ccRCC alter chromatin context resulting in oncogenic retargeting of HIF1 and HIF2. We propose to identify differentially regulated HIF targeting sites and affected transcripts to identify individual genes or collections of genes that are specifically associated with pathological HIF stabilization. We furthermore propose to examine the individual contributions of histone methylation modifier genes and members of the chromatin remodeling complex recently identified as mutated in commonly in ccRCC to this retargeting and explore the implications in human tumor chromatin packaging.
This proposal examines the interrelationships between epigenetic modification of chromatin and HIF transcriptional activation in cancer. We propose to identify differentially regulated HIF targeting sites and affected transcripts to identify individual genes or collections of genes that are specifically associated with pathological HIF stabilization. We furthermore propose to examine the individual contributions of histone methylation modifier genes and members of the chromatin remodeling complex recently identified as mutated in commonly in ccRCC to this retargeting and explore the implications in human tumor chromatin packaging.
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