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.