SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines. [Display omitted] •Colon-to-ileum mucosal conversion in SATB2 mutant mice and human organoids•SATB2 maintains colonic identity of stem and differentiated cells•Ectopic SATB2 converts ileum to colon•SATB2 regulates enhancer binding of CDX2 and HNF4A Gu et al. show that the adult colonic mucosa has a surprising degree of plasticity, regulated by the chromatin factor SATB2. Loss of SATB2 in mice or in human colonic organoids leads to transformation of the colonic mucosa to small intestine ileum with marked morphological, functional, and epigenetic remodeling.