Project 3: Oncogenic triggers and their influence on 3D chromosomal architecture

项目 3：致癌触发因素及其对 3D 染色体结构的影响

• 批准号: 10652283
• 负责人: Iannis Aifantis
• 金额: $ 41.18万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-12 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652283
• 关键词: 3-Dimensional; Acute T Cell Leukemia; Address; Affect; Animal Disease Models; Animal Model; Architecture; Area; B-Lymphocytes; Binding; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CREBBP gene; Cells; Chromatin; Chromatin Loop; Chromatin Structure; Chromosomal Loss; Chromosome Structures; Code; Complement; Complex; DNA; DNA Methylation; DNA Modification Process; DNA analysis; Defect; Development; Disease; Disease Progression; Drug Combinations; Drug Targeting; EP300 gene; EZH2 gene; Elements; Enhancers; Epigenetic Process; Event; Evolution; Experimental Leukemia; Gene Expression; Gene Expression Regulation; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Growth; Hematopoietic Neoplasms; Histones; Human; In Vitro; Leukemic Cell; MYC Family Protein; Malignant Neoplasms; Maps; Mutate; Mutation; NOTCH1 gene; Oncogenes; Oncogenic; Organizational Change; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Proteins; RNA; Recurrence; Role; Signal Pathway; Somatic Mutation; Study models; T-Cell Leukemia; T-Lymphocyte; Testing; Tumor Suppressor Proteins; Untranslated RNA; Xenograft procedure; antileukemic activity; cancer cell; cohesin; epigenetic regulation; epigenome; gamma secretase; genome-wide; histone modification; human model; in vivo; inhibitor; leukemia; leukemia initiating cell; leukemia/lymphoma; neoplastic cell; next generation sequencing; novel; overexpression; programs; promoter; protein expression; response; targeted treatment; three dimensional structure; transcription factor; tumor; tumor progression

SUMMARY – PROJECT 3 (AIFANTIS) Recent studies have offered the first comprehensive maps of three-dimensional (3D) chromosomal interactions. The 3D structure of chromatin is defined in part by the organization of chromatin into highly conserved topologically associating domains (TADs). Studies presented in Project 1 and 2 directly address the role of key “structural” elements of TAD boundaries (CTCF/Cohesin) in human cancer, including B cell and T cell malignancy (leukemia and lymphoma). In Project 3, we will test the hypothesis that 3D chromatin structure is not only affected by CTCF/Cohesin alterations but also by mutations that affect specific epigenetic regulators and by oncogenic transcription factors. For these studies, we will use T cell leukemia (T-ALL), as a model of study. We will test whether T-ALL oncogenes (the transcription factor NOTCH1, the main driver in this disease, mutated or activated in 90% of human T-ALL) use 3D DNA looping events to induce expression of gene- targets and non-protein coding RNAs that control the function of leukemia cells, including cells that can initiate the disease (leukemia initiating cells), that are characterized by the overexpression of the NOTCH1 transcriptional target MYC. In addition to oncogenic (NOTCH1, MYC) activation, chromosomal topology can also be influenced by epigenetic regulators, and it was shown that T-ALL is a disease characterized by recurrent inactivating mutations in genes that can affect DNA and histone modifications, including genes that affect DNA methylation (DNMT3A), promoter (EZH2) and enhancer (EP300) activity. We thus hypothesize that in human leukemia oncogenes (NOTCH1) and tumor suppressors (DNMT3A, EZH2, EP300) cause aberrant 3D chromatin organization changes and that targeted drug treatments are able to correct these defects. We test this hypothesis in three Aims. Aim 1 assesses the ability of oncogenes like NOTCH1 to directly alter CTCF/Cohesin distribution leading to aberrant chromosomal architecture. Aim 2 tests the hypothesis that drugs that target either oncogenic signaling pathways (NOTCH pathway inhibitors) or altered epigenetic states (BET inhibitors, targeting active H3K27ac-marked areas) can correct 3D chromosomal structure. Finally, Aim 3 focuses on potential effects of selected T-ALL somatic mutations targeting epigenetic regulators and examines their impact on chromosomal topology. We believe that these studies will complement Projects 1 and 2 that focus on the impact of CTCF/Cohesin alterations in blood cancer and generate new paradigms of gene expression regulation in human leukemia.

摘要--项目3(Aifantis) 最近的研究提供了第一个全面的三维(3D)染色体图谱 互动。染色质的3D结构部分由染色质的高度组织来定义 保守的拓扑结合结构域(TADS)。项目1和2中提出的研究直接涉及 包括B细胞和T细胞在内的TAD边界关键“结构”元件(CTCF/Coherin)在人类癌症中的作用 细胞恶性肿瘤(白血病和淋巴瘤)。在项目3中，我们将测试3D染色质结构的假设 不仅受到CTCF/粘附素改变的影响，还受到影响特定表观遗传调控因子的突变的影响 以及致癌转录因子。在这些研究中，我们将使用T细胞白血病(T-ALL)作为 学习。我们将测试T-ALL癌基因(转录因子NOTCH1，这种疾病的主要驱动因素， 在90%的人类T-ALL中突变或激活)使用3D DNA循环事件来诱导基因- 控制白血病细胞功能的靶标和非蛋白质编码RNA，包括可以启动 以NOTCH1过度表达为特征的疾病(白血病启动细胞) 转录靶标MYC。除了致癌(NOTCH1，MYC)激活外，染色体拓扑还可以 也受到表观遗传调节因子的影响，研究表明T-ALL是一种具有以下特征的疾病 可影响DNA和组蛋白修饰的基因的反复失活突变，包括 影响DNA甲基化(DNMT3A)、启动子(EZH2)和增强子(EP300)的活性。因此，我们假设 在人类白血病中，癌基因(NOTCH1)和肿瘤抑制基因(DNMT3A、EZH2、EP300)导致异常 3D染色质组织发生变化，靶向药物治疗能够纠正这些缺陷。我们 从三个方面来检验这一假设。目的1评估像NOTCH1这样的癌基因直接改变 CTCF/粘附素分布导致染色体构型异常。《目标2》验证了药物 靶向致癌信号通路(Noch通路抑制物)或改变的表观遗传状态(BET 针对活性H3K27ac标记区域的抑制剂)可以纠正3D染色体结构。最后，目标3 重点关注针对表观遗传调节因子的选定T-ALL体细胞突变的潜在影响并进行检查 它们对染色体拓扑的影响。我们认为，这些研究将补充项目1和项目2 关注CTCF/粘附素改变在血癌中的影响并产生新的基因范例 人类白血病中的表达调控。