Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b

Abstract

The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here we report that the T-UCR enhances intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b). Decreasing the levels of by gene silencing led to dysfunction of the intestinal epithelial barrier in cultured cells and increased the vulnerability of the gut barrier to septic stress in mice. specifically stimulated translation of the tight junction (TJ) claudin-1 (CLDN1) by associating with miR-29b rather than by binding directly to mRNA. acted as a natural decoy RNA for miR-29b, which interacts with mRNA via the 3' untranslated region and represses its translation. Ectopically expressed abolished the association of miR-29b with mRNA and restored claudin-1 expression to normal levels in cells overexpressing miR-29b, thus rescuing the barrier function. These results highlight a novel function of in controlling gut permeability and define a mechanism by which stimulates claudin-1 translation, by decreasing the availability of miR-29b to mRNA.

Long Noncoding RNA H19 Impairs the Intestinal Barrier by Suppressing Autophagy and Lowering Paneth and Goblet Cell Function

“…3 Intestinal epithelial cells (IECs), connected by apical intercellular junctional complexes named tight junctions (TJs) and adherens junctions (AJs), establish a selectively permeable barrier that protects the subepithelial tissue against luminal noxious substances, but they also react to noxious stimuli by secreting different antimicrobial peptides and proteins. 4,5 Paneth cells that reside at the bottom of the crypts produce high quantities of defensins and other antibiotic proteins such as lysozyme, Reg3 lectins, and phospholipase A2 when exposed to pathogenic bacteria and bacterial products such as lipopolysaccharide (LPS). 6 In response to bacterial infection of the intestines, Paneth cells secrete lysozyme through secretory autophagy 7 and their function is tightly regulated at the posttranscriptional level by the RNA binding protein HuR.…”

“…15,16 Recent evidence has indicated that lncRNAs are an emerging class of master regulators of intestinal epithelium homeostasis and participate in the control of gut permeability, mucosal growth, and adaptation. 5,[17][18][19] Transcribed from the conserved imprinted H19/igf2 gene cluster, lncRNA H19 is implicated in different cellular processes. 20,21 During embryogenesis, H19 expression levels increase in extraembryonic tissues, in the embryo itself, and in most fetal tissues, but its levels decrease after birth.…”

“…The concentration of the FITC dextran in the basal medium was determined using a fluorescence plate reader with an excitation wavelength of 490 nm and an emission wavelength of 530 nm. TEER was measured with an epithelial voltmeter under open-circuit conditions (WPI, Sarasota, FL) as described, 5 and the TEER of all monolayers was normalized to that of control monolayers in the same experiment.…”

Unveiling ncRNA regulatory axes in atherosclerosis progression

“…In this sense, it was seminal the report of a direct interaction of Uc.283+A with pri‐miR‐195 that prevented the cleavage of this last by Drosha and hindered its maturation [193]. Subsequently, other authors have described further T‐UCR/miRNA interactions such as that of Uc.173 with miRNA‐195 [194] or miR‐29b [195] to facilitate function of the intestinal epithelium, or the interaction of Uc.416+A with miR‐153 in renal cell carcinoma [189].…”

Highlighting transcribed ultraconserved regions in human diseases

“…The silencing of uc.173 causes dysfunction in the intestinal epithelial barrier by inhibiting the claudin‐1 protein, which is important to determine the permeability of this tissue. The regulatory action of uc.173 is also caused by the decoy RNA effect for miR‐29b, which represses claudin‐1 translation (J. Y. Wang et al, ).…”