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

项目总结 这项拟议的研究职业发展计划旨在调查DNA的影响 基因组组织的低甲基化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人员 麻省总医院病理科研究员。这项建议 包含项目所需的特定技术技能，包括培训 先进的显微方法、CRISPR技术和重复元素生物学。结构化的 职业发展计划包括实验室管理、科学和技术方面的培训和指导 领导力、研究沟通、拨款撰写和其他关键的职业技能。这些技术 职业技能将在布拉德利·伯恩斯坦博士的指导下获得，他将担任 主要导师，并有在学术界获得小组组长职位的学员的历史，如 以及由凯瑟琳·伯恩斯博士等世界级科学家组成的研究咨询委员会， 吴婷、基思·荣格和尼尔·哈科恩。通过这一综合计划，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 独立的内科科学家教员职位，实验室专注于基本机制和 癌症表观遗传学中的治疗机会。 DNA低甲基化是一种表观遗传学改变，存在于大多数实体肿瘤中，但其功能 后果没有明确定义。DNA去甲基化治疗在临床上得到广泛应用 用于治疗骨髓增生异常综合征和一组白血病，最近被 可能通过激活ERV使肿瘤细胞对免疫疗法敏感。尽管 这一点，DNA低甲基化和ERV激活的功能后果仍然不清楚。 这个项目探索了候选人在最近的基因组研究中发现的机制基础 原发结肠肿瘤的组织结构。这一结果将DNA低甲基化与 与肿瘤抑制相关的染色质隔间的组织 转录程序，包括诱导ERV。这项建议的目的是：(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 上调是低甲基化和隔室重组之间的机械联系，并 (3)确定下游转录程序的影响。这些研究将揭示小说 影响肿瘤细胞特性的表观遗传机制，并为部署 在新的临床环境中进行去甲基化治疗，以利用 DNA低甲基化。

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.