Chromatin maintenance in cancer progression

癌症进展中的染色质维持

• 批准号: 9248144
• 负责人: Ian J Davis
• 金额: $ 21.74万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248144
• 关键词: Chromatin; maintenance; cancer; progression

 DESCRIPTION (provided by applicant): Mutations in chromatin regulatory proteins have recently been identified in a wide range of human cancers. Although these mutations are associated with disease progression, how they contribute to tumorigenesis remains unknown. We propose to investigate SETD2, a non-redundant histone methyltransferase that preferentially places a trimethylation mark on Histone H3 on lysine 36 in actively transcribed gene bodies. This gene is mutated in approximately 15% of renal cell carcinomas, and is being identified in a growing list of tumors. By examining chromatin organization in primary human tumors, we observed that SETD2 mutation and loss of its histone modification were associated with changes in nucleosome accessibility and widespread alteration in RNA processing. We hypothesize that histone mark dysregulation through SETD2 loss is an important component of tumorigenesis. We propose a highly collaborative project that employs biochemical, genetic and genomic approaches to comprehensively explore the effect of SETD2 mutation on chromatin and transcription, in an effort to unravel the mechanisms by which SETD2 loss leads to the promotion of cancer. To this end, we have generated a unique set of cell-based model systems which uses comparative genomic studies between human and yeast cells. We have additionally established novel domain-specific activities of SETD2, and the first demonstration of functional mutations separating di-methylating from tri-methylating activity. We propose three complementary aims: 1) to define the chromatin reprogramming and transcriptional effects of SETD2 mutation, revealing critical mechanistic features that link histone modification and nucleosome position to the transcriptional and DNA repair defects associated with SETD2 loss, 2) to utilize the separation of function revealed by high severity SETD2 mutants in the catalytic (SET) domain and the RNA polymerase II interactions domain (SRI) to reveal important determinants of the genomic phenotype, and 3) to explore discrete functions associated with SETD2 loss mediated by the altered H3K36me3 mark, by systematically examining the histone "reader" molecules that transduce signals for DNA methylation, DNA repair, and transcriptional elongation. Taken together, these studies will define the mechanistic link between SETD2 loss of function and cancer development, as well as reveal novel opportunities for biomarker or therapeutic interventions.

 描述（由申请人提供）：最近在多种人类癌症中发现了染色质调节蛋白的突变。虽然这些突变与疾病进展有关，但它们如何促进肿瘤发生仍然未知。我们建议调查SETD2，一个非冗余的组蛋白甲基转移酶，优先放置在组蛋白H3上的赖氨酸36在活跃转录的基因体的三甲基化标记。该基因在大约15%的肾细胞癌中发生突变，并且正在越来越多的肿瘤中被鉴定。通过检查原发性人类肿瘤中的染色质组织，我们观察到SETD2突变及其组蛋白修饰的丢失与核小体可及性的变化和RNA加工的广泛改变相关。我们推测，通过SETD 2丢失的组蛋白标记失调是肿瘤发生的重要组成部分。我们提出了一个高度合作的项目，该项目采用生化、遗传和基因组方法全面探索SETD 2突变对染色质和转录的影响，以努力解开SETD 2缺失导致癌症促进的机制。为此，我们已经生成了一套独特的基于细胞的模型系统，该系统使用人类和酵母细胞之间的比较基因组研究。我们还建立了新的结构域特异性活动的SETD 2，并首次证明功能突变分离二甲基化从三甲基化的活动。我们提出三个相辅相成的目标：1）定义SETD 2突变的染色质重编程和转录效应，揭示将组蛋白修饰和核小体位置与SETD 2丢失相关的转录和DNA修复缺陷联系起来的关键机制特征，2）利用由催化（SET）结构域和RNA聚合酶II相互作用结构域中的高严重性SETD2突变体揭示的功能分离（SRI）揭示基因组表型的重要决定因素，3）通过系统地检查组蛋白“阅读器”分子来探索与改变的H3K36me3标记介导的SETD2损失相关的离散功能，所述组蛋白“阅读器”分子抑制DNA甲基化、DNA修复和转录延伸的信号。总之，这些研究将确定SETD 2功能丧失与癌症发展之间的机制联系，并揭示生物标志物或治疗干预的新机会。