Stem cells of the gut epithelium constantly produce precursors that progressively undergo a succession of molecular changes resulting in growth arrest and commitment to a specific differentiation program. Few transcriptional repressors have been identified that maintain the normal intestinal epithelial cell (IEC) proliferation state. Herein, we show that the nuclear receptor co-repressor (NCoR1) is differentially expressed during the proliferation-to-differentiation IEC transition. Silencing of NCoR1 expression in proliferating cells of crypt origin resulted in a rapid growth arrest without associated cell death. A genechip profiling analysis identified several candidate genes to be up-regulated in NCoR1-deficient IEC. Pigment epitheliumderived factor (PEDF, also known as serpinf1), a suspected tumor suppressor gene that plays a key role in the inhibition of epithelial tissue growth, was significantly up-regulated in these cells. Chromatin immunoprecipitation experiments showed that the PEDF gene promoter was occupied by NCoR1 in proliferating epithelial cells. Multiple retinoid X receptor (RXR) heterodimers interacting sites of the PEDF promoter were confirmed to interact with RXR and retinoid acid receptor (RAR). Cotransfection assays showed that RXR and RAR were able to transactivate the PEDF promoter and that NCoR1 was repressing this effect. Finally, forced expression of PEDF in IEC resulted in a slower rate of proliferation. These observations suggest that NCoR1 expression is required to maintain IEC in a proliferative state and identify PEDF as a novel transcriptional target for NCoR1 repressive action.The intestinal epithelium consists of a cell monolayer organized in crypts and villi. This epithelium is under constant and rapid renewal, which is assured by constant division of the stem cells located at the base of the crypts (1). The descendant progenitor cells are progressively instructed to differentiate to exert their functional role during their journey along the villus compartment (2). The proliferation-to-differentiation transition of single progenitor cell is tightly regulated by morphogens, growth factors and hormones that impact on intracellular signaling pathways. Molecular alterations of specific components from these different classes of molecules are suspected to be important during the development of intestinal cancer (3).In vivo studies have demonstrated the role of steroid hormones and ligands during intestinal epithelial development and homeostasis (4). For example, the thyroid hormone exerts a positive effect on gut mucosal maturation (5) and enterocyte differentiation (6, 7). Members of the nuclear hormone receptor superfamily are activated by metabolically transformed lipids that are absorbed by intestinal epithelial cells (IEC) 4 before interacting with their receptors and associated gene targets (8). Peroxisome proliferator-activated receptors (PPARs) are welldescribed examples of lipophilic ligand binding transcription factors that can influence intestinal epithelial proliferati...