Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer

Cancer has been characterized as a wound that does not heal. Malignant cells are morphologically distinct from normal proliferating cells but have extensive similarities to tissues undergoing wound healing and/or regeneration. The mechanistic basis of this similarity has, however, remained enigmatic. Here we show that the genomic region upstream of Myc, which is required for intestinal tumorigenesis, is also required for intestinal regeneration after radiation damage. The region is also critical for growth of adult intestinal cells in 3-D organoid culture, indicating that culture conditions that recapitulate most aspects of normal tissue architecture still reprogram normal cells to proliferate using a mechanism similar to that employed by cancer cells. Our results uncover a genetic link between tissue regeneration and tumorigenesis, and establish that normal tissue renewal and regeneration of tissues after severe damage are mechanistically distinct. Crypt enriched fractions of adult mouse intestine or organoids from fetal intestine of wild-type and mice with deletion of the MYC regulatory region were analysed with scRNA-seq. Adult mice with or without 12 Gy irradiation were used. Intestines were collected 2 days after irradiation (2dpi) for scRNA-seq. For fetal organoid 3Dcultures, epithelium was harvested from E16.5 intestine and cultured in matrigel. Single cell suspensions were prepared on day 11 of culture. Wild-type cultures predominantly contained budding organoids with mature crypt like structures and few small dense sheroids. These were separately picked and analysed. These did not show major differences and were considered as WT1 and WT2 respectively. The 3D cultures from the mutant mice only contained large spherical structures.