AbstractThe long non-coding RNAEPRis expressed in epithelial tissues, binds to chromatin and controls distinct biological activities in mouse mammary gland cells. Because of its high expression in the intestine, in this study we have generated a colon-specific conditional targeted deletion (EPRcKO) to evaluateEPR in vivofunctions in mice.EPRcKO mice display epithelium hyperproliferation, impaired mucus production and secretion, as well as inflammatory infiltration in the proximal portion of the large intestine. RNA sequencing analysis reveals a rearrangement of the colon crypt transcriptome with strong reduction of goblet cell-specific factors including those involved in the synthesis, assembly, transport and control of mucus proteins. Further, colon mucosa integrity and permeability are impaired inEPRcKO mice, and this results in higher susceptibility to dextran sodium sulfate (DSS)-induced colitis and tumor formation. HumanEPRis down-regulated in human cancer cell lines as well as in human cancers, and overexpression ofEPRin a colon cancer cell line results in enhanced expression of pro-apoptotic genes. Mechanistically, we show thatEPRdirectly interacts with select genes involved in mucus metabolism whose expression is reduced inEPRcKO mice and thatEPRdeletion causes tridimensional chromatin organization changes.