Integrated analyses of the epigenome to understand the molecular basis of hematopoietic malignancies

表观基因组的综合分析以了解造血系统恶性肿瘤的分子基础

• 批准号: 10360961
• 负责人: Avi Srivastava
• 金额: $ 8.97万
• 依托单位: NEW YORK GENOME CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360961
• 关键词: Address; Awareness; Bone Marrow; Cancer Biology; Cell Differentiation process; Cell Surface Proteins; Cell physiology; Cells; Chromatin; Computer Models; Computing Methodologies; Data; Development; Development Plans; Enhancers; Environment; Epigenetic Process; Event; Gene Expression; Genetic Transcription; Genome; Goals; Grouping; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Histones; Impairment; Investigation; Learning; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Measurement; Mentorship; Modality; Modeling; Molecular; Mus; New York; Occupations; Pattern; Peripheral Blood Mononuclear Cell; Pilot Projects; Play; Polycomb; Process; Regulator Genes; Regulatory Element; Repression; Research; Research Personnel; Research Project Summaries; Research Proposals; Role; Scientist; System; Technology; Training; Transferase; Variant; Wild Type Mouse; anti-cancer; base; career; career development; cell fate specification; cell type; computational suite; computer framework; computerized tools; design; epigenome; epigenomics; experimental study; gene regulatory network; hematopoietic differentiation; histone methylation; histone methyltransferase; histone modification; improved; in silico; leukemia; loss of function; mouse model; multidisciplinary; multimodality; novel; promoter; single cell proteins; single cell technology

PROJECT SUMMARY Research Plan: An impaired hematopoietic differentiation process underlies bone marrow malignancies like leukemia, but we still lack the mechanistic understanding of the sequence of regulatory events that misleads the differentiation process. Since epigenomic regulatory patterns are major features of leukemic development, understanding the chromatin dynamics of a failed (malignant) hematopoietic differentiation process can help define the molecular basis of leukemia. A prerequisite to such an understanding is a framework that allows investigation of the progressive changes in the activity of the regulatory elements (RE) during hematopoietic differentiation. Single-cell CUT&Tag (scCUT&Tag) technology is well-suited for such studies as RE activity through histone modification profiles can be investigated in a lineage-specific manner. However, poor understanding of the cell-type-specific histone modification patterns makes the task challenging. To overcome this challenge, we designed scCUT&Tag-pro which allows simultaneous measurement of cell-surface protein and in-silico integration of gene-expression and chromatin accessibility. I will leverage this novel multimodal framework to investigate the RE and progressive changes in their activity during hematopoiesis. First, I will define a multimodal reference mapping framework for mouse hematopoiesis. This framework will allow me to integrate multiple histone modification profiles onto one reference and compare the chromatin states of the RE between a wild type (WT) and mouse model with loss of function in histone methyl transferase (HMT) (Aim 1). Second, since HMTs regulate transcription through the interaction network of RE. I will define a chromatin state aware map that dynamically links REs across developmental trajectories. I will use this framework to investigate the changes in the interaction of REs due to HMT loss (Aim 2). Third, since the transcriptional state of a cell emerges from the underlying gene regulatory network (GRN), I will integrate single-cell gene expression data with histone modification profiles and extend it to define a chromatin state aware model of GRN. I will compare the WT and HMT loss experiments and define the differential GRN (Aim 3). Altogether, this research proposal seeks to pioneer the computational methods for the integrated analyses of multimodal single-cell histone modifications and systematically dissect progressive changes in the system-level function of the regulatory circuits that misleads hematopoietic differentiation using mouse models with conditional HMT loss of function in the hematopoietic compartment. I have developed a 5-year career development plan to meet my goal of becoming an independent investigator in the multi-disciplinary field of computational cancer biology. The mentorship committee will also provide me the guidance in my research and academic job search. Given the excellent the outstanding record of training multiple independent scientists, New York Genome Center provides me an ideal environment to attain my scientific career goals.

项目摘要 研究计划：造血分化过程受损是骨髓恶性肿瘤的基础 白血病，但我们仍然缺乏对误导监管事件顺序的机械理解 分化过程。由于表观基因质调节模式是白血病发育的主要特征，因此 了解失败（恶性）造血分化过程的染色质动力学可以帮助 定义白血病的分子基础。这种理解的先决条件是一个允许的框架 调查造血期间调节元素（RE）活性的进行性变化 分化。单细胞切割和标签（SCCUT＆TAG）技术非常适合RE活动等研究 通过组蛋白的修饰曲线可以以特异性方式研究。但是，贫穷 了解细胞型特异性组蛋白修饰模式使任务具有挑战性。克服 这项挑战，我们设计了SCCUT＆TAG-PRO，允许同时测量细胞表面蛋白 以及基因表达和染色质可及性的核内整合。我将利用这个新颖的多模式 研究造血期间其活性的RE和逐渐变化的框架。首先，我将定义 小鼠造血的多模式参考映射框架。这个框架可以让我整合 多个组蛋白修饰轮廓到一个参考，并比较RE之间的染色质状态 野生型（WT）和小鼠模型，在组蛋白甲基转移酶（HMT）中的功能损失（AIM 1）。第二， 由于HMT通过RE的相互作用网络调节转录。我将定义染色质状态 映射该映射将RES跨发育轨迹链接。我将使用此框架调查 由于HMT损失引起的RES相互作用的变化（AIM 2）。第三，由于细胞的转录状态出现 从基础基因调节网络（GRN）中，我将将单细胞基因表达数据与组蛋白整合在一起 修改轮廓并将其扩展以定义GRN的染色质状态意识模型。我将比较wt和 HMT损失实验并定义差异GRN（AIM 3）。总之，这项研究提案试图 先驱，用于多模式单模蛋白修饰的集成分析的计算方法 并系统地剖析了调节电路系统级功能的进行性变化 使用小鼠模型误导造血分化，该模型有条件HMT在 造血室。我已经制定了一项为期5年的职业发展计划，以实现我的目标 计算癌生物学多学科领域的独立研究者。指导 委员会还将在我的研究和学术求职中为我提供指导。鉴于优秀 培训多个独立科学家的杰出记录，纽约基因组中心为我提供了理想 实现我的科学职业目标的环境。