H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR

Abstract

The disruption of the intestinal epithelial barrier function occurs commonly in various pathologies, but the exact mechanisms responsible are unclear. The H19 long noncoding RNA (lncRNA) regulates the expression of different genes and has been implicated in human genetic disorders and cancer. Here, we report that H19 plays an important role in controlling the intestinal epithelial barrier function by serving as a precursor for microRNA 675 (miR-675). H19 overexpression increased the cellular abundance of miR-675, which in turn destabilized and repressed the translation of mRNAs encoding tight junction protein ZO-1 and adherens junction E-cadherin, resulting in the dysfunction of the epithelial barrier. Increasing the level of the RNA-binding protein HuR in cells overexpressing H19 prevented the stimulation of miR-675 processing from H19, promoted ZO-1 and E-cadherin expression, and restored the epithelial barrier function to a nearly normal level. In contrast, the targeted deletion of HuR in intestinal epithelial cells enhanced miR-675 production in the mucosa and delayed the recovery of the gut barrier function after exposure to mesenteric ischemia/reperfusion. These results indicate that H19 interacts with HuR and regulates the intestinal epithelial barrier function via the H19-encoded miR-675 by altering ZO-1 and E-cadherin expression posttranscriptionally.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01030-15.

ACKNOWLEDGMENTS

This work was supported by a Merit Review Award (to Jian-Ying Wang) from the U.S. Department of Veterans Affairs, grants from National Institutes of Health (DK57819, DK61972, and DK68491 to Jian-Ying Wang), and funding from the National Institute on Aging-Intramural Research Program, NIH (to Myriam Gorospe). Jian-Ying Wang is a Senior Research Career Scientist, Biomedical Laboratory Research & Development Service, U.S. Department of Veterans Affairs.