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: 9754580
• 负责人: Ali Shilatifard
• 金额: $ 79.71万
• 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/9754580
• 关键词: Biochemical; Biological Models; Cataloging; Catalogs; 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（由申请人证明）：我们的研究集中在蛋白质的set1 /mll家族的分子功能和生化特性上，以及嵌合体和突变与儿童白血病和其他形式的癌症如何相关。染色质和转录伸长机械在发育基因表达的调节中的作用以及如何对thair vities的造成不利的作用，这将使我们对基于NT的基于NT和基于突变的癌症的理解能够促进表观遗传调节剂4。在组蛋白H3（H3K4）中，我们证明了果蝇细胞具有三个与甲基化组蛋白H3K4的蛋白质相关的蛋白质和哺乳动物LS的六个蛋白质。 ，这是l易解为许多无关的基因，导致白血病的发病机理是同一大分子的一部分。这些基因的检查中的基因，触发了白血病的生长，癌症癌症中癌症中癌症中癌症的癌症的近期分组MALIGNAGNANC和实体肿瘤很少。参与癌症的发病机理R的更多目的是靶向治疗的目标。在发育的调节中，以及mut突变如何促进humancancer的发病机理。