The Epigenetic Regulator PHF16 Redresses Homeostasis During Intestinal Injury Repair [RNA-seq]

The intestinal stem cells (ISCs) are highly vulnerable to DNA damage, being in a constant state of proliferation1. Reserve crypt stem cells restore homeostatic intestinal epithelium following damage-induced ablation of ISCs2-5. Here, we report that the epigenetic regulator PHD finger protein 16 (PHF16) redresses revival stem cell (revSC) activity after damage repair. Phf16-/Y mice showed defects in exit from the regenerative state of revSCs and failed in intestinal crypt regeneration, while they still induced revSCs in response to tissue damage, as observed using single-cell RNA-sequencing. RNA-sequencing and ATAC-sequencing analyses of Phf16-/Y intestinal organoids revealed that PHF16 controls intestinal epithelial differentiation by promoting HBO1-mediated histone H3K14 acetylation, while PHF16 also counteracts YAP/TAZ activity by ubiquitination of CDC73, faithfully reverting damage-induced revSCs to homeostatic gut epithelial cells. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.