Diet-induced chromatin states influence intestinal stem cell memory

SUMMARY Intestinal stem cells (ISCs) integrate dietary cues through a metabolic–transcriptional axis, but whether these mechanisms create a lasting epigenetic memory remains unclear. Here, we investigate diet-induced chromatin adaptations in ISCs using a high-fat Western diet (HFD) mouse model. HFD broadly remodels chromatin accessibility, altering pre-existing open regulatory regions. Many differentially accessible regions (DARs) persist during the differentiation of ISCs into transient amplifying cells (TACs). Notably, HFD-induced DARs are retained following diet normalization despite phenotypic reversibility, and HFD re-exposure enhances ISC self-renewal and adenoma growth compared with naïve HFD exposure. The HFD-induced chromatin changes require Ppar-d/a nuclear receptors but are independent of their transcriptional targets. Although a subset of HFD-induced DARs is maintained following Apc loss, extensive chromatin remodeling driven by tumor suppressor inactivation largely overrides diet-dependent differences in Lgr5 ⁺ ISCs. Together, these findings demonstrate that ISCs retain a chromatin-based memory of dietary fat exposure.