Research Specialist Support-Targeting DNA Methylation and the Cancer Epigenome

项目摘要/摘要 刘敏民博士和小组主任Peter A.Jones博士自2012年以来一直密切合作，并产生了 在癌症表观遗传学领域产生重大影响的大量高质量出版物。 刘博士发现，在癌细胞中，用维生素C或G9Ai(G9a赖氨酸甲基转移酶)治疗 抑制剂)协同增强DNA甲基转移酶抑制剂(DNMTi)5-aza-CDR的作用。这个 其基本机制是通过增加内源性逆转录病毒(ERV)的表达和激活 抗病毒干扰素反应，抑制癌细胞生长并导致细胞凋亡。这些发现引发了 她有兴趣进一步探索重复元件(包括ERV)在癌症免疫信号和 了解它们在癌细胞中表达的分子机制。因为她的研究表明 ERV是表观遗传治疗的重要靶点，这一领域的进一步研究可能会推动 开发靶向疗法，提高癌症治疗的疗效。 这项建议的目的是支持刘博士作为一名研究专家的职业发展 对琼斯博士已建立的研究项目做出了重大贡献，该项目由NCI资助。刘博士目前 回答以下问题。1)为什么染色质修饰物有这么多突变，是什么 这些突变对表观基因组结构的影响？2)双链RNA(如 ERV)被5-aza-cdr激活，这些与细胞反应有何关系？3)我们能设计 可能提高5-氮杂核苷治疗效果的表观遗传药物组合？目标 她未来的研究是确定ERV在癌症免疫信号中的作用，并确定 他们的表情。这些项目将为我们从整体上理解表观基因组提供新的见解 将导致新的策略，增加患者对表观遗传疗法的反应。这一奖项将使 刘博士有自由和安全地推进她的癌症表观遗传学研究，并支持 琼斯小组的研究计划。

PROJECT SUMMARY / ABSTRACT Dr. Minmin Liu and the Unit Director, Dr. Peter A. Jones, have worked closely since 2012 and have generated a significant number of high-quality publications that have had a major impact on the field of cancer epigenetics. Dr. Liu made the discovery that in cancer cells, treatment with vitamin C or G9Ai (G9A lysine methyltransferase inhibitor) synergistically enhances the effects of 5-aza-CdR, a DNA methyltransferase inhibitor (DNMTi). The underlying mechanism is through increased expression of endogenous retroviruses (ERVs) and activation of an anti-viral interferon response, which inhibits cancer cell growth and causes apoptosis. These findings sparked her interest in further exploring the roles of repetitive elements (including ERVs) in cancer immune signaling and in understanding the molecular mechanisms of their expression in cancer cells. Because her studies suggest that ERVs are important targets of epigenetic therapy, further research in this area is likely to advance the development of targeted therapies that have improved efficacy in cancer treatment. The objective of this proposal is to support Dr. Liu's career development as a research specialist in making significant contributions to Dr. Jones' established research program, which is funded by NCI. Dr. Liu is currently addressing the following questions. 1) Why are there so many mutations in chromatin modifiers, and what are the effects of these mutations on the structure of the epigenome? 2) What double-stranded RNAs (such as ERVs) are activated by 5-aza-CdR and how do these relate to cellular responses? 3) Can we design combinations of epigenetic drugs that might increase the effectiveness of 5-azanucleoside treatment? The aims for her future studies are to define the roles of ERVs in cancer immune signaling and to identify regulators for their expression. These projects will provide new insights for our understanding of the epigenome holistically and will lead toward novel strategies that increase patient response to epigenetic therapies. This award will enable Dr. Liu to have the freedom and security to advance her research in cancer epigenetics and to support the research program of the Jones group.