My scientific goal is to understand how cell biological processes are disrupted to promote tumorigenesis and genomic instability, with a particular focus on how cells properly segregate their genomes during mitosis. I am investigating mechanisms by which the tumor suppressor SETD2 is required for proper chromosome structure/organization and chromosome-cytoskeleton attachment during cell division. SETD2 has long been known to methylate histone 3 (H3) to regulate gene transcription, RNA splicing and DNA damage repair. I have recently identified that SETD2 is also required for organization of centromeres, or the centers of individual chromosomes, which are the sites of microtubule (MT) attachment during mitosis. Loss of SETD2 causes changes in “centromere identity,” i.e. where and how centromeres are built on chromosomes. We find that, in SETD2 mutants, centromere levels increase and new centromeres form at ectopic sites throughout chromosomes, both of which cause chromosome segregation errors. Thus, SETD2 regulates both MTs dynamics as well as how and where MTs attach to chromosomes, underscoring how important SETD2 is as a tumor suppressor. Importantly, we also identified that loss of SETD2 correlate with disruption in telomeres, which may also precipitate chromosome instability. To investigate how chromosome missegregation drives aneuploidy, tumorigenesis and tumor heterogeneity, I utilize a number of optical, cell biological, and biochemical approaches, with an emphasis on live and fixed imaging coupled with computational image analyses for in vitro, in situ, and in vivo systems. My expertise as a cell biologist has given me a unique approach and skill set to determine how the basic, fundamental process of centromere identity could be co-opted by tumor cells to drive aneuploidy, intratumor heterogeneity and evade therapeutic interventions.