Chromatin maintenance in cancer progression

癌症进展中的染色质维持

基本信息

批准号：
9150499
负责人：
Ian J Davis
金额：
$ 45.97万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9150499
关键词：
Biochemical Biochemical Genetics Biological Markers Biological Models C-terminal Cancer Cell Growth Regulation Cells Childhood Acute Lymphocytic Leukemia Chromatin Clear Cell DNA Damage DNA Methylation DNA Modification Methylases DNA Repair DNMT3a Data Defect Development Disease Disease Progression Dissection Double Strand Break Repair Environment Event Frequencies Future Genes Genetic Transcription Genome Genomic Instability Genomic approach Genomics Growth Histone H3 Histones Human Individual Kidney Neoplasms Link Lysine Maintenance Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Mediator of activation protein Messenger RNA Modeling Mutate Mutation Neoplasm Metastasis Nucleosomes Orthologous Gene Pathway interactions Pattern Phenotype Positioning Attribute Process Property Proteins RNA Polymerase II RNA Processing RNA Splicing Reader Refractory Regulation Regulator Genes Renal Cell Carcinoma Renal carcinoma Reporting Research Personnel Role SET Domain Severities Signal Transduction Structure-Activity Relationship Testing Therapeutic Therapeutic Intervention Transcript Transcription Process Transcriptional Regulation Tumor Cell Biology Tumor Suppression Yeasts base cancer cell comparative genomics functional genomics genetic approach genetic regulatory protein high risk histone methylation histone methyltransferase histone modification homologous recombination kidney cell loss of function metaplastic cell transformation mutant neoplastic cell novel nuclease programs public health relevance repaired response tumor tumor progression tumorigenesis

项目摘要

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（由适用提供）：最近在广泛的人类癌症中鉴定出染色质调节蛋白的突变。尽管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。我们建议研究一种非冗余的组蛋白甲基转移酶SetD2，优先在主动转录的基因体中在赖氨酸36上对组蛋白H3上的三甲基化标记。该基因在大约15％的肾细胞癌中被突变，并且正在越来越多的肿瘤清单中鉴定出来。通过检查原发性人类肿瘤中的染色质组织，我们观察到SETD2突变和其组蛋白修饰的丧失与RNA加工中核能可及性和广泛变化的变化有关。我们假设组蛋白通过setD2损失是肿瘤发生的重要组成部分。我们已经建立了一个高度协作的项目，该项目采用生化，遗传和基因组方法来全面探索SETD2突变对染色质和转录的影响，以揭示SETD2损失导致促进癌症的机制。为此，我们生成了一组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SETD2的新型域特异性活性，并首次证明了将二甲基与三甲基活性分开的功能突变。我们提出了三个完整的目标：1）定义setD2突变的染色质重编程和转录效应，揭示了关键的机械特征，这些特征将组蛋白修饰和核小体位置与转录和DNA修复缺陷联系起来，与setD2损失相关的转录和DNA修复缺陷，2）以利用高dectd2突变体（SETD 2）的分离（set 2 （SRI）通过系统地检查了与由改变的H3K36me3标记介导的SETD2损耗相关的离散功能的基因组表型的重要决定剂，并通过系统地检查了组蛋白“读取器”分子，这些分子是传输DNA甲基化，DNA修复，DNA修复，DNA修复，DNA修复，DNA修复，DNA修复，DNA修复和转录质量。综上所述，这些研究将定义SETD2功能丧失与癌症发展之间的机械联系，并揭示了生物标志物或治疗干预措施的新机会。