Project Summary This proposal is a renewal of a prior R50 grant that supported the bioinformatics needs of cancer researchers at Northwestern University. The initial award primarily supported two NCI funded Outstanding Investigators, Dr. Marcus Peter and Dr. Ali Shilatifard, with a small fraction of support for the Robert H. Lurie Comprehensive Cancer Center. Now, Dr. Bartom has become the Scientific Associate Director for Bioinformatics for the Cancer Center, and she will support a broader array of research programs for different cancer center members. The Unit Director for this proposal is Dr. Leon Platanias, PI of the Cancer Center. A specific area of note will continue to be Dr. Marcus Peter’s investigations into the role of 6mer seed toxicity in the body’s natural defenses against cancer, and how this mechanism can be activated in order to improve outcomes for cancer patients. She will also continue to work with colleagues within the Simpson Querrey Center for Epigenetics, including Dr. Ali Shilatifard, to understand how genetic changes in the machinery of chromatin regulation can lead to epigenetic mutations and defects in gene activation and transcriptional elongation. Research into the molecular dynamics in primary human cell cultures infected with Kaposi’s Sarcoma-associated Herpesvirus will continue with Dr. Eva Gottwein, giving insight into how Kaposi’s Sarcomas arise in AIDS patients. All three of these investigators are cancer center members, whose research is supported by the Cancer Center P30 grant. The common thread in all of these projects is the need for careful, biologically motivated computational analysis to make sense of next generation sequencing data that is essential in examining the function of cells, both before and after cancer development and before and after pharmaceutical perturbation. Dr. Bartom will provide this analysis, and her expertise in both biology and computation will allow cancer biologists to extract more insight from their data, and to maintain a high standard of scientific rigor and reproducibility.