LncRNAEPRregulates intestinal mucus production and protects against inflammation and tumorigenesis

Abstract

The long non-coding RNA EPR is 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 (EPR cKO) to evaluate EPR in vivo functions in mice. EPR cKO 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 in EPR cKO mice, and this results in higher susceptibility to dextran sodium sulfate (DSS)-induced colitis and tumor formation. Human EPR is down-regulated in human cancer cell lines as well as in human cancers, and overexpression of EPR in a colon cancer cell line results in enhanced expression of pro-apoptotic genes. Mechanistically, we show that EPR directly interacts with select genes involved in mucus metabolism whose expression is reduced in EPR cKO mice and that EPR deletion causes tridimensional chromatin organization changes.

Functional roles of conserved lncRNAs and circRNAs in eukaryotes

“…LncRNAs have been reported to exert their functions by chromatin remodeling [ 11 , 16 , [55] , [56] , [57] , [58] ]. For instance, the lncRNA EPR ( E pithelial cell P rogram R egulator) is prominently expressed in epithelial tissues such as the mammary gland, gastrointestinal tract, lung, and kidney [ 57 , 58 ].…”

“…LncRNAs have been reported to exert their functions by chromatin remodeling [ 11 , 16 , [55] , [56] , [57] , [58] ]. For instance, the lncRNA EPR ( E pithelial cell P rogram R egulator) is prominently expressed in epithelial tissues such as the mammary gland, gastrointestinal tract, lung, and kidney [ 57 , 58 ]. In both human and mice, the EPR level is significantly decreased in breast cancer cell lines compared to normal mammary gland cells and EPR overexpression reduces breast cancer cell proliferation [ 57 ].…”

The Regulated Secretion and Models of Intracellular Transport: The Goblet Cell as an Example

“…In goblet cells exhibiting breaks of the APM, distal (situated near the APM) SGs usually lost their electron density. Long stacks with wells, the absence of ERES, and COPII-coated buds on the rough ER cisternae, the pure development of CMC, and the absence of TMC were discovered as a result of studying images presented in the literature and the analysis of images from the preparation and submission of an article by Briata et al [25]. Starting from the 3-4th cisternae, distensions began to form.…”

“…This indicates that, even for membranes where mucin accumulates, GGE and nuclear sugar transporters are lost. SG membranes form close contacts forming a pentalamellar structure instead of a heptalamellar one [25]. SGs can also fuse [12].…”

“…In the current review, we study the literature and our residual data concerning the structure of the GC and the mechanisms of transport through it in goblet cells, where protein secretion is organized according to RS through a wide APM. Additionally, we use some data presented during the submission stage of two our papers [24,25] and pay further attention to the aspects of the cellular and tissue biology of goblet cells, since the molecular aspects are perfectly described in the excellent studies of Gustafsson et al [26,27].…”