Mutations of Chromatin and its Modifying Machineries in Malignancies

恶性肿瘤中染色质及其修饰机制的突变

• 批准号: 10224897
• 负责人: Ali Shilatifard
• 金额: $ 91.97万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-13 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224897
• 关键词: Biochemical; Biological Models; Cataloging; Cells; Childhood Leukemia; Chimera organism; Chromatin; Chromatin Remodeling Factor; Complex; Development; Developmental Gene Expression Regulation; Drosophila genus; Epigenetic Process; Family; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Histone H3; Histones; Human; Laboratories; Lysine; MLL gene; Macromolecular Complexes; Malignant Neoplasms; Mammalian Cell; Molecular; Mutate; Mutation; Names; Pathogenesis; Positioning Attribute; Property; Protein Family; Proteins; Reagent; Role; Sequence Homology; Solid Neoplasm; Somatic Mutation; Transcription Elongation; Yeasts; base; leukemia; public health relevance; targeted treatment; tool

 DESCRIPTION (provided by applicant): Our studies have focused on the characterization of the molecular functions and biochemical properties of the Set1/MLL family of proteins and how their chimeras and mutations are associated with childhood leukemia and other forms of cancer. We have also focused on the role of chromatin and transcriptional elongation machinery in the regulation of developmental gene expression and how the misregulation of their activities is associated with malignancies. Our hope is that our molecular studies will advance our understanding of the molecular mechanisms of rearrangement-based and mutation-based cancer through the epigenetic regulators. Our biochemical and molecular studies demonstrated that Set1 in yeast exists in the Set1/COMPASS complex capable of methylating lysine 4 of histone H3 (H3K4). We demonstrated that Drosophila cells possess three Set1-related proteins and mammalian cells have six Set1-related proteins all found within COMPASS-like compositions capable of methylating histone H3K4. Furthermore, given that there is almost no sequence homology between many of the MLL translocation partners, for many years, it was unclear why MLL translocations into so many unrelated genes result in the pathogenesis of leukemia. Our biochemical studies on the purification of the MLL-chimeras demonstrated that many of the MLL translocation partners are part of the same macromolecular complex we named the Super Elongation Complex (SEC). We demonstrated that the translocations of MLL within any of the subunits of SEC subunits result in the misrecruitment of SEC to the MLL target genes and in the perturbation of the transcriptional checkpoint control of these genes, triggering leukemic growth. Additionally, the recent cataloging of somatic mutations in cancer identified a large number of mutations in the components of the MLL1-4 and Set1A/B complexes in both hematological malignancies and solid tumors. However, we know very little why the COMPASS family is mutated in different cancers. Given that we have developed a fantastic set of reagents and tools over the past seventeen years towards these factors and their associated proteins, chromatin, and other chromatin modifiers in multiple model systems; my laboratory is in a very unique position to define the molecular bases of these factors' involvement in cancer pathogenesis for the purpose of targeted therapeutics. Therefore, the goals of this R35 application is the full molecular and biochemical characterization of the COMPASS family, the translocation partners within the Super Elongation Complex (SEC), and the role of chromatin itself in the regulation of gene expression and development, and how their mutations contribute to the pathogenesis of human cancer.

 描述（由申请人提供）：我们的研究集中在Set 1/MLL蛋白家族的分子功能和生化特性的表征以及它们的嵌合体和突变如何与儿童白血病和其他形式的癌症相关。我们还关注了染色质和转录延伸机制在发育基因表达调控中的作用，以及它们的活性失调如何与恶性肿瘤相关。我们的希望是，我们的分子研究将通过表观遗传调节因子促进我们对基于重复和基于突变的癌症的分子机制的理解。我们的生物化学和分子生物学研究表明，酵母中的Set 1存在于Set 1/COMPASS复合物中，能够甲基化组蛋白H3的赖氨酸4（H3 K4）。我们证明，果蝇细胞具有三个Set 1相关的蛋白质和哺乳动物细胞有六个Set 1相关的蛋白质都发现在COMPASS样组合物能够甲基化组蛋白H3 K4。此外，鉴于许多MLL易位伴侣之间几乎没有序列同源性，多年来，尚不清楚为什么MLL易位到如此多的不相关基因中导致白血病的发病机制。我们对MLL-嵌合体纯化的生物化学研究表明，许多MLL易位伴侣是我们命名为超延伸复合物（SEC）的相同大分子复合物的一部分。我们证明了MLL在SEC亚基的任何亚基内的易位导致SEC向MLL靶基因的错误募集以及这些基因的转录检查点控制的扰动，从而触发白血病生长。此外，最近对癌症中体细胞突变的分类鉴定了血液恶性肿瘤和实体瘤中MLL 1 -4和Set 1A/B复合物组分中的大量突变。然而，我们对COMPASS家族在不同癌症中发生突变的原因知之甚少。鉴于我们在过去的十七年中已经开发了一套非常棒的试剂和工具，用于多模型系统中的这些因子及其相关蛋白质，染色质和其他染色质修饰剂;我的实验室处于一个非常独特的位置，可以定义这些因子参与癌症发病机制的分子基础，以实现靶向治疗的目的。因此，该R35应用的目标是COMPASS家族的完整分子和生物化学表征，超级延伸复合物（SEC）内的易位伴侣，染色质本身在基因表达和发育调控中的作用，以及它们的突变如何有助于人类癌症的发病机制。