Characterizing heterochromatin dysfunction as a driving alteration in cancer

将异染色质功能障碍描述为癌症的驱动改变

• 批准号: 10653138
• 负责人: Jason Huse
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653138
• 关键词: ATRX gene; Address; Automobile Driving; Behavior; Binding Proteins; Biological; Biological Process; Biology; Brain Neoplasms; Cancer Biology; Cancerous; Cell Line; Cells; Chromatin; Collaborations; Complex; Confocal Microscopy; Coupled; DNA; DNA Damage; Data; Development; Developmental Gene; Elements; Epigenetic Process; Event; Evolution; Functional disorder; G-Quartets; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Genomic Instability; Glioma; Gliomagenesis; Heterochromatin; Histone Deacetylase; Histones; Human Cell Line; In Vitro; Isocitrate Dehydrogenase; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microscopic; Microscopy; Modeling; Molecular; Mouse Cell Line; Mus; Mutation; Normal Cell; Normal tissue morphology; Nuclear Lamina; Nucleosomes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Predisposition; Primary Brain Neoplasms; Process; Proteins; Publishing; Reagent; Recurrence; Regulation; Regulator Genes; Research; Role; Signal Pathway; Site; Stretching; Structure; System; Thalassemia; Therapeutic; Therapeutically Targetable; Variant; Work; X-Linked Mental Retardation; body system; cell motility; chromatin protein; combat; design; epigenetic profiling; epigenomic profiling; epigenomics; genetic approach; genome-wide; glioma cell line; in vivo; insight; mutant; nervous system development; nondeletion type alpha-thalassemia/mental retardation syndrome; novel; permissiveness; programs; replication stress; resistance mechanism; stem cells; therapeutic target; treatment strategy; tumor; tumorigenesis

PROJECT SUMMARY Recent research has emphatically confirmed that cancer is characterized not only by mutations in genes, but also by disturbances in gene regulation. This latter mechanism often involves chromatin—the proteins and regulatory molecules directly associated with DNA—and their influence on gene expression through so-called “epigenetic” effects. Inactivation of the chromatin regulator protein ATRX (-thalassemia mental retardation X- linked) is commonly seen in several cancer variants, including malignant glioma, the most common and deadly primary brain cancer. While ATRX has been implicated in a variety of biological processes in normal cells, its role in cancer biology is less clear. In our recent work, we confirmed that ATRX deficiency dramatically alters chromatin and underlying gene expression, while also rendering DNA more susceptible to damage, breakage, and other abnormalities. In particular, we found that ATRX loss disrupts the organization of specific regions of chromatin, called heterochromatin, where key developmental genes undergo systematic silencing as organ systems mature. Prior work by other groups suggests that heterochromatin dysfunction, and loss of underlying gene silencing, contributes to cancer development. The central hypothesis of our proposal is that disruptions in heterochromatin promote glioma formation by altering gene expression and inducing damage and abnormalities in DNA. In this project, we will address our central hypothesis using customized human and mouse cell lines that recapitulate the core biological and molecular features of ATRX-deficient glioma, along with bona fide glioma cell lines, with and without ATRX deficiency, derived directly from patients. Some of our studies will incorporate glioma models in mice. Furnished with these reagents, we will conduct epigenetic profiling, coupled with microscopy and molecular and cell biological approaches, to correlate chromatin-related findings with cancerous behaviors. In our first aim, we will characterize the mechanisms by which ATRX deficiency alters heterochromatin in glioma. In our second aim, we will delineate the extent to which heterochromatin dysfunction in ATRX-deficient glioma promotes damage and abnormalities in DNA. Finally, in our third aim, we will identify key gene expression changes associated with ATRX deficiency that drive cancerous behavior in glioma and investigate mechanisms by which they can be therapeutically targeted. If successful, our work will characterize an entirely novel molecular process driving cancer formation and provide insights into treatment strategies for deadly brain tumors.

项目总结 最近的研究已经强调证实，癌症的特征不仅是基因突变，而且 基因调控方面的干扰也是如此。后一种机制通常涉及染色质--蛋白质和 与DNA直接相关的调节分子--以及它们通过所谓的 “表观遗传”效应。染色质调节蛋白ATRX(-地中海贫血-智力低下X- )通常见于几种癌症变种，包括最常见和最致命的恶性胶质瘤 原发脑癌。虽然ATRX参与了正常细胞的各种生物学过程，但其 在癌症生物学中的作用还不是很清楚。在我们最近的工作中，我们证实ATRX缺乏会显著改变 染色质和潜在基因的表达，同时也使DNA更容易受到损伤，断裂， 以及其他异常情况。特别是，我们发现ATRX的丢失扰乱了特定区域的组织 染色质，称为异染色质，其中关键的发育基因作为器官经历系统的沉默 系统成熟了。其他研究小组之前的工作表明，异染色质功能障碍和潜在的 基因沉默，有助于癌症的发展。我们提议的中心假设是，干扰 异染色质通过改变基因表达和诱导损伤促进胶质瘤的形成 DNA的异常。在这个项目中，我们将使用定制的人类和 概括ATRX缺陷性胶质瘤核心生物学和分子特征的小鼠细胞系，以及 用真正的胶质瘤细胞系，有或没有ATRX缺乏，直接来自患者。我们的一些人 研究将纳入小鼠的胶质瘤模型。有了这些试剂，我们将进行表观遗传学 结合显微镜和分子和细胞生物学方法的图谱分析，以关联染色质相关 癌症行为的发现。在我们的第一个目标中，我们将描述ATRX 在胶质瘤中，缺乏改变异染色质。在我们的第二个目标中，我们将描述 ATRX缺乏的胶质瘤中的异染色质功能障碍会促进DNA的损伤和异常。最后，在 我们的第三个目标是，我们将确定与ATRX缺乏相关的关键基因表达变化 胶质瘤的癌变行为，并研究其治疗靶点的机制。如果 成功后，我们的工作将描述一种全新的推动癌症形成的分子过程，并提供 对致命脑瘤治疗策略的见解。