Cancer recurrence and resistance to radiation and chemotherapy are two of the most vexing challenges in cancer treatment, resulting in burgeoning healthcare costs and, more problematically, fatalities every year. A contributing factor is the natural and stress-induced emergence of a subpopulation of tumor cells which is resistant to treatment, often entering into a special cellular state called quiescence (G0). G0 cells have a distinct transcriptional program through which they acquire new properties including long life, thrifty metabolism and resistance to stress. None of the current therapies specifically target these tumor cells. To address this knowledge, my lab modeled G0 in fission yeast and showed that as cells transition to G0, constitutive heterochromatin proteins are deployed to several euchromatic regions to regulate the expression of developmental, metabolic and cell cycle genes. This work suggested (1) a new function for constitutive heterochromatin proteins in establishing the global transcriptional program of eukaryotic cells in response to long-term stress. Moreover, unexpectedly we also found that many of the genes coregulated by heterochromatin factors in G0 are found in linear gene arrays, enriched for specific biological processes (BPs), such as metabolism, cell cycle and proliferation. This led us to hypothesize that (2) clustering of disparate BP genes may be a conserved organizing principle in eukaryote genomes for efficient coregulation of thousands of genes in response to stress or developmental programs. Recently we tested both predictions of our model experimentally and computationally. In today’s talk, I will present some of our latest findings which demonstrate that modeling quiescence in the fission yeast revealed novel, conserved principles in transcriptional regulation in eukaryotes with application in cancer biology.