Epigenetics, Metabolism and Cancer

项目摘要 现在普遍认为，表观遗传和代谢因素是肿瘤发生的主要驱动因素， 将是癌症治疗的核心。表观遗传学和 代谢最容易通过表观遗传修饰剂的辅因子实现，表观遗传修饰剂是代谢的关键输入和产物。 代谢途径乙酰辅酶A，除了在氧化磷酸化中的作用外， 组蛋白乙酰基转移酶使用的乙酸盐。S-腺苷蛋氨酸，由叶酸和蛋氨酸产生 代谢途径，是组蛋白和DNA甲基化的供体。α-酮戊二酸，一种TCA循环代谢物， 是Jumonji和LSD家族的组蛋白脱甲基酶以及10 - 11易位酶的辅因子 (TET)参与DNA去甲基化的泰特甲基胞嘧啶双加氧酶家族。之间的直接链路 癌症代谢和表观遗传途径的一个重要方面是鉴定异柠檬酸脱氢酶的突变 IDH 1和IDH 2在骨髓恶性肿瘤中的作用，也经常表现出TET 2突变。IDH突变是 发现是功能获得性突变，将α-酮戊二酸转化为D（R）-2-羟基戊二酸， 泰特酶。基于表观遗传学和代谢在肿瘤发生中的深刻关系， 越来越多的方法来调查这些过程，我们建议建立一个及时的，严格的，和状态- 西北大学范伯格医学院的最先进的培训计划， 获得知识和技能，发展自己的生产性癌症研究计划。该计划将 介绍创新课程结合课堂作业和实验室工作在表观遗传学，代谢和相关数据 分析能力。学员将有一个单独的培训计划，其中将包括共同导师，以充分涵盖 开展表观遗传学和新陈代谢之间的桥梁项目所需的广泛专业知识。此外，本发明还 优秀的研究人员，由学员主持，将被带到西北医学全年 涵盖表观遗传学和新陈代谢的主题。每年的研究日将由内部和外部 顾问成员进行监督和提供建议，以确保培训计划的成功。尽管受训者将 培训补助金只能支持两年，我们强烈鼓励所有培训补助金的毕业生 继续在他们的博士后生涯中参与许多这些活动。基于强 西北大学对表观遗传学和代谢的投资，该计划的跟踪记录 教师，并在这一计划的机构投资，有很大的潜力，促进 培养癌症表观遗传学和代谢方面的杰出未来研究人员。

Project Summary It is now well accepted that epigenetic and metabolic factors are major drivers of tumorigenesis and the link between the two pathways will be central in cancer therapy. The intimate connection between epigenetics and metabolism is most readily realized by the cofactors for epigenetic modifiers being key inputs and products for metabolic pathways. Acetyl coenzyme A, in addition to its role in oxidative phosphorylation, is the source of acetate used by histone acetyltransferases. S-adenosyl methionine, produced by the folate and methionine metabolic pathways, is the donor for histone and DNA methylation. Alpha ketoglutarate, a TCA cycle metabolite, is a cofactor for histone demethylases of the Jumonji and LSD families, as well as for the ten-eleven translocase (TET) Tet methylcytosine dioxygenase family that is involved in DNA demethylation. A direct link between the metabolic and epigenetic pathways in cancer was the identification of mutations in isocitrate dehydrogenases IDH1 and IDH2 in myeloid malignancies, which also frequently exhibits TET2 mutations. The IDH mutations were found to be gain-of-function mutations, converting alpha ketoglutarate to D(R)-2-hydroxyglutarate, which inhibits the TET enzymes. Based on the deep relationship of epigenetics and metabolism in tumorigenesis and the growing number of methods to investigate these processes, we propose to create a timely, rigorous, and state- of-the-art training program at Northwestern University Feinberg School of Medicine to allow postdoctoral fellows to gain the knowledge and skills to develop their own productive cancer research programs. The program will introduce innovative courses combining classwork and lab work in epigenetics, metabolism, and related data analysis skills. Trainees will have an individual training plan, which will include co-mentors to fully cover the broad expertise needed for carrying out projects that bridge epigenetics and metabolism. Additionally, outstanding investigators, hosted by trainees, will be brought to Northwestern Medicine throughout the year covering topics in epigenetics and metabolism. An annual research day will be joined by internal and external advisory members to monitor and advise to ensure the success of this training program. Although trainees will only be supported by the training grant for two years, we strongly encourage all graduates of the training grant to continue to participate in many of these activities throughout their postdoctoral career. Based on the strong investment of Northwestern University into epigenetics and metabolism, the track record of the program's preceptors, and the institutional investments in this program, there is great potential for facilitating the development of outstanding future investigators in cancer epigenetics and metabolism.