Chromatin organization and transcription factor targeting in cancer

描述（由申请人提供）：缺氧途径信号传导与癌症发展之间的联系与肾细胞癌的关系最为密切。缺氧，组织中氧含量的减少，导致转录因子缺氧诱导因子1（HIF 1）和缺氧诱导因子2（HIF 2）的稳定，其通常导致遗传程序的转录激活，从而导致短暂的代谢适应。在人类透明细胞肾细胞癌（ccRCC）中，该途径被Von Hippel Lindau基因（VHL）中的突变所选择，VHL通常在正常氧水平的条件下介导HIF的快速蛋白体降解。在没有VHL活性的情况下，HIF在缺氧条件下积累，易位到细胞核并激活转录程序。然而，缺氧诱导的HIF转录程序与异常HIF表达相关的HIF转录程序并不相同。导致这些转录因子重靶向的机制尚不清楚。然而，最近的深度测序工作已经确定了编码表观遗传调节因子的基因中的复发性突变，包括染色质重塑复合物成员和修饰组蛋白的酶。这些事件的复发性表明它们与癌症发展相关，而不是旁观者突变。然而，这些突变在ccRCC中的作用仍然未知。我们假设在ccRCC中鉴定的表观遗传调节因子的突变改变了染色质背景，导致HIF 1和HIF 2的致癌重靶向。我们建议鉴定差异调节的HIF靶向位点和受影响的转录本，以鉴定与病理性HIF稳定性特异性相关的单个基因或基因集合。 我们还建议检查组蛋白甲基化修饰基因和染色质重塑复合物的成员最近被确定为在ccRCC中常见突变的个体贡献，并探索人类肿瘤染色质包装的影响。

DESCRIPTION (provided by applicant): 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 transcriptio 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 individul 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.