Homeostatic control of stem cell activity during intestinal regeneration

Stem cells proliferate rapidly to maintain tissue turnover during regeneration, yet the mechanisms preventing hyperproliferation remain unclear. Here, we identified nuclear factor Y (NF-Y) as a transcriptional repressor that maintains intestinal stem cell (ISC) quiescence. NF-Y restricts ISC proliferation by occupying the promoters of epidermal growth factor receptor (EGFR) signaling components, including Egfr , Mkp3 , Raf , Ras , and pnt , through regulation dependent on the histone acetyltransferase Nejire (Nej)/p300. Loss of NF-Y enhances ISC proliferation and accelerates tumor progression. NF-Y acts with Nej to restrict Egfr expression and suppress hyperproliferation. Together, these results demonstrate that NF-Y, acting with Nej, serves as a key transcriptional repressive brake that restrains growth-signaling to control stem cell activity under homeostatic and disease conditions.