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.

成体干细胞通过产生组织特异性后代来维持再生组织结构和功能，但保持其组织特性的因素尚不清楚。小肠和大肠的细胞组成和功能明显不同，反映了它们不同的干细胞群。在这里，我们表明 SATB2 是一种结肠限制性染色质因子，在小鼠和人类中单独保留 LGR5 ⁺成体结肠干细胞和上皮特性。卫星二号成年小鼠的损失导致结肠干细胞稳定转化为小肠回肠样干细胞，并用类似于回肠的细胞替代结肠粘膜。相反，SATB2 赋予小鼠回肠结肠特性。人结肠类器官在 SATB2 丢失后也具有回肠特征。SATB2 部分通过调节肠道转录因子 CDX2 和 HNF4A 的增强子结合来调节结肠特性。我们的研究揭示了一种保守的结肠干细胞核心调节因子，能够介导成熟肠道的跨组织可塑性。