Elucidating the impact of DNA hypomethylation on genome organization and anti-tumor transcriptional programs

阐明 DNA 低甲基化对基因组组织和抗肿瘤转录程序的影响

• 批准号: 10457023
• 负责人: Sarah E Johnstone
• 金额: $ 10.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457023
• 关键词: Academia; Advisory Committees; Architecture; Belief; Biology; Burn injury; CRISPR/Cas technology; Cell Aging; Cell Nucleus; Cell model; Cell physiology; Cells; Cessation of life; Chromatin; Clinic; Clinical; Clinical Pathways; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Colon Carcinoma; Colonic Neoplasms; Communication Research; CpG Islands; DNA; DNA Methylation; DNA Sequence Alteration; Development Plans; Dysmyelopoietic Syndromes; Elements; Endogenous Retroviruses; Engineering; Epigenetic Process; Euchromatin; Faculty; Foundations; Future; Gene Silencing; General Hospitals; Genes; Genetic Transcription; Genome; Genomic DNA; Genomic Segment; Genomics; Grant; Heterochromatin; Hypermethylation; Immunity; Immunotherapy; Kinetics; Laboratories; Leadership; Link; Malignant - descriptor; Malignant Neoplasms; Massachusetts; Mediating; Mentors; Mentorship; Methods; Methylation; Microscopy; Modeling; Normal Cell; Nuclear; Oncogenic; Pathology; Peripheral; Pharmaceutical Preparations; Phenotype; Physicians; Play; Positioning Attribute; Professional Competence; Program Development; Reagent; Recording of previous events; Repetitive Sequence; Research; Research Proposals; Role; Scientist; Solid Neoplasm; Structure; Technical Expertise; Testing; Therapeutic; Training; Tumor Immunity; Tumor Suppressor Genes; United States; Up-Regulation; Work; Writing; cancer testis antigen; career development; cellular engineering; checkpoint therapy; colon cancer patients; gene repression; genome-wide; in vitro Model; insight; leukemia; neoplastic cell; novel; programs; skills; stemness; tool; tumor

PROJECT SUMMARY This proposed research career development program seeks to investigate the impact of DNA hypomethylation on genome organization and the mechanisms by which it drives downstream tumor suppressive transcriptional programs. The candidate is currently a clinical and research fellow in the Department of Pathology of the Massachusetts General Hospital. The proposal incorporates specific technical skills that will be required for the project including training in advanced microscopy methods, CRISPR techniques and repetitive element biology. The structured career development plan includes training and mentorship in laboratory management, scientific leadership, research communication, grant writing, and other critical career skills. These technical and career skills will be acquired under the guidance of Dr. Bradley Bernstein, who will serve as primary mentor and has a history of trainees that obtain group leader positions in academia, as well as a Research Advisory Committee of world-class scientists including Drs. Kathleen Burns, Ting Wu, Keith Joung and Nir Hacohen. Through this comprehensive program the candidate will acquire a unique set of clinical and research skills that will enable her to transition to an independent physician scientist faculty position with a lab focused on basic mechanisms and therapeutic opportunities in cancer epigenetics. DNA hypomethylation is an epigenetic alteration found in most solid tumors, but its functional consequences are not clearly defined. DNA demethylating therapies are widely used in the clinic for treatment of myelodysplastic syndrome and a subset of leukemias, and have recently been shown to sensitize tumor cells to immunotherapy, possibly through activation of ERVs. Despite this, the functional consequences of DNA hypomethylation and ERV activation remain obscure. This project explores the mechanistic basis of findings in the candidate’s recent study of genome organization in primary colon tumors. The results link DNA hypomethylation to striking changes in the organization of chromatin compartments that are associated with tumor suppressive transcriptional programs, including induction of ERVs. The aims of this proposal are to: (1) Investigate if DNA hypomethylation causes chromatin reorganization, (2) test if massive ERV upregulation is a mechanistic link between hypomethylation and compartment reorganization and (3) determine impact of downstream transcriptional programs. These studies will uncover novel epigenetic mechanisms that impact tumor cell identity and lay the foundation for deploying demethylating therapies in new clinical settings to harness tumor-suppressive consequences of DNA hypomethylation.

项目摘要 这项拟议的研究职业发展计划旨在调查DNA的影响 低甲基化对基因组组织的影响及其驱动下游的机制 肿瘤抑制转录程序。候选人目前是一名临床和研究 他是马萨诸塞州总医院病理科的研究员。该提案 包含项目所需的特定技术技能，包括以下方面的培训 先进的显微镜技术，CRISPR技术和重复元件生物学。结构化 职业发展计划包括实验室管理、科学研究、 领导力、研究沟通、资助写作和其他关键职业技能。这些技术 和职业技能将在布拉德利伯恩斯坦博士的指导下获得， 主要导师，并有学员的历史，获得小组领导人的立场，在学术界， 以及包括凯瑟琳·伯恩斯博士在内的世界级科学家组成的研究咨询委员会， Ting Wu，基思·乔姆斯基和尼尔·哈科恩。通过这一全面的计划，候选人将 获得一套独特的临床和研究技能，使她能够过渡到一个 独立的医生科学家教师职位，实验室专注于基本机制， 癌症表观遗传学的治疗机会。 DNA低甲基化是在大多数实体瘤中发现的表观遗传学改变，但其功能性改变可能与肿瘤的发生有关。 后果没有明确界定。DNA去甲基化疗法在临床上应用广泛 用于治疗骨髓增生异常综合征和一部分白血病， 显示可能通过ERV的活化使肿瘤细胞对免疫疗法敏感。尽管 因此，DNA低甲基化和ERV活化的功能结果仍然不清楚。 这个项目探讨了候选人最近对基因组研究中发现的机制基础 原发性结肠肿瘤中的组织。这些结果将DNA低甲基化与细胞内 与肿瘤抑制相关的染色质区室的组织 转录程序，包括ERV的诱导。本提案的目的是：（1） 研究DNA低甲基化是否导致染色质重组，（2）检测是否存在大量ERV 上调是低甲基化和区室重组之间的机械联系， (3)确定下游转录程序的影响。这些研究将揭示新的 影响肿瘤细胞身份的表观遗传机制，并为部署 在新的临床环境中进行去甲基化治疗， DNA低甲基化。