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: 10402273
• 负责人: Iannis Aifantis
• 金额: $ 32.45万
• 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/10402273
• 关键词: 3-Dimensional; Acute T Cell Leukemia; Address; Affect; Animal Disease Models; Animal Model; Architecture; Area; B-Lymphocytes; Binding; Bromodomain; CREBBP gene; Cells; Chromatin; Chromatin Loop; Chromatin Structure; Chromosomal Loss; Chromosome Structures; Code; Complement; Complex; DNA; DNA Methylation; DNA Modification Process; DNA analysis; Defect; Disease; Disease Progression; Drug Combinations; Drug Targeting; EP300 gene; EZH2 gene; Elements; Enhancers; Epigenetic Process; Event; Evolution; 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.

概要-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， 交互.染色质的3D结构部分地由染色质组织成高密度结构来定义。 保守拓扑关联结构域（TADs）。项目1和项目2中的研究直接针对 肿瘤边界的关键“结构”元件（CTCF/Cohesin）在人类癌症（包括B细胞和T细胞）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 不仅受CTCF/粘附素改变的影响，还受影响特定表观遗传调节因子的突变的影响 和致癌转录因子。对于这些研究，我们将使用T细胞白血病（T-ALL）作为模型， study.我们将测试T-ALL癌基因（转录因子NOTCH 1，这种疾病的主要驱动因素， 在90%的人T-ALL中突变或激活）使用3D DNA成环事件来诱导基因表达， 控制白血病细胞功能的靶点和非蛋白质编码RNA，包括可以启动 以NOTCH 1过表达为特征的疾病（白血病起始细胞） 转录靶MYC。除了致癌（NOTCH 1、MYC）激活外，染色体拓扑结构还可以 也受到表观遗传调节因子的影响，研究表明，T-ALL是一种特征为 基因中的复发性失活突变可影响DNA和组蛋白修饰，包括 影响DNA甲基化（DNMT 3A）、启动子（EZH 2）和增强子（EP 300）活性。因此，我们假设 人白血病癌基因（NOTCH 1）和肿瘤抑制基因（DNMT 3A、EZH 2、EP 300）引起异常 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 在三个目标中检验这个假设。目的1评估NOTCH 1等癌基因直接改变 CTCF/粘着蛋白分布导致染色体结构异常。目标2检验了药物 靶向致癌信号通路（NOTCH通路抑制剂）或改变的表观遗传状态（BET 抑制剂，靶向活性H3 K27 ac标记的区域）可以纠正3D染色体结构。第三，目标 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，并检查 对染色体拓扑结构的影响我们认为，这些研究将补充项目1和2， 专注于CTCF/粘附素改变在血癌中的影响，并产生新的基因范式 在人类白血病中的表达调控。