Chromatin organization and transcription factor targeting in cancer

在肾细胞癌中，低氧信号通路与癌症发生发展之间的关系最为密切。低氧是组织中氧含量的减少，导致转录因子低氧诱导因子1(HIF1)和低氧诱导因子2(HIF2)的稳定，这通常导致基因程序的转录激活，从而导致瞬时代谢适应。在人类透明细胞肾细胞癌(CcRCC)中，这一途径被Von Hippel Lindau基因(VHL)突变所取代，VHL基因通常在正常氧气水平下介导HIF的快速蛋白酶体降解。在没有VHL活性的情况下，HIF在低氧条件下积聚，移位到细胞核并激活转录程序。然而，缺氧诱导的HIF转录程序与与HIF异常表达相关的HIF转录程序并不完全相同。导致这些转录因子重定向的机制尚不清楚。然而，最近的深度测序工作发现了编码表观遗传调节因子的基因的反复突变，包括染色质重塑复合体成员和修饰组蛋白的酶。这些事件的反复发生表明，它们与癌症的发展有关，而不是旁观者的突变。然而，这些突变在ccRCC中的作用仍不清楚。我们假设，在ccRCC中发现的表观遗传调节因子的突变改变了染色质环境，导致HIF1和HIF2的致癌重定向。我们建议确定差异调控的HIF靶点和受影响的转录本，以确定与病理性HIF稳定相关的单个基因或基因集合。 此外，我们还建议检查组蛋白甲基化修饰基因和最近被发现在ccRCC中常见的突变的染色质重塑复合体成员对这种重定向的单独贡献，并探索其在人类肿瘤染色质包装中的意义。

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.