Tet governs transcriptional programs required for intestinal stem cell development and homeostasis

Yet, the intrinsic mechanisms driving divergent developmental trajectories of seemingly homogeneous progenitors, directing some to establish adult ISCs and others to differentiate, remain unclear. Here, we identify Tet as an essential transcriptional regulator of ISC establishment.

Developmental Tet depletion causes region-specific ISC loss and compromises adult lifespan, while adult-specific loss drives progressive stem cell exhaustion. Overexpression of Tet leads to ISC expansion in both developing and adult guts. Utilizing a comprehensive single-nucleus transcriptomic atlas spanning gut development, we demonstrate that Tet stabilizes progenitor identity by maintaining epithelial integrity, signaling competence, and fate maintenance.