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Diet-dependent nutrient availability influences how intestinal stem cells (ISC) produce differentiated cells with altered oncogenic capacity. Investigating mechanisms by which environmental nutrients reprogram ISCs may inform novel approaches for preventing colorectal cancer. In their study, Choi and colleagues integrated RNA-sequencing, ATAC-sequencing, functional genomic approaches, and imaging to study ISC dynamics in response to new Western-style diet 1 (NWD1), which contains nutrients at levels that increase CRC risk in humans. Integrated RNA- and ATAC-sequencing as well as imaging revealed that NWD1 decreases RNA and protein expression of Pgc1a—a master mitochondrial biogenesis regulator—by limiting accessibility to an enhancer in Lgr5^hi ISCs. Eliminating Pgc1a in Lgr5^hi ISCs via Cre-lox recombination abrogated oxidative phosphorylation in vivo, altering Lgr5^hi ISC differentiated cell production as measured by single-cell RNA-sequencing. In situ hybridization identified a corresponding emergence of Bmi1⁺Ascl2^hi ISCs above crypts in NWD1-fed mice. Single-cell RNA-sequencing suggested NWD1 promotes...