Abstract
ABSTRACTInterferon (IFN) signaling is key to mucosal immunity in the gastrointestinal tract, but cellular regulatory elements that determine interferon gamma (IFN-γ)-mediated antimicrobial defense in intestinal epithelial cells are not fully understood. We report here that a long noncoding RNA (lncRNA), GenBank accession no. XR_001779380, was increased in abundance in murine intestinal epithelial cells following infection by Cryptosporidium, an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children. Expression of XR_001779380 in infected intestinal epithelial cells was triggered by TLR4/NF-κB/Cdc42 signaling and epithelial-specific transcription factor Elf3. XR_001779380 primed epithelial cells for IFN-γ-mediated gene transcription through facilitating Stat1/Swi/Snf-associated chromatin remodeling. Interactions between XR_001779380 and Prdm1, which is expressed in neonatal but not adult intestinal epithelium, attenuated Stat1/Swi/Snf-associated chromatin remodeling induced by IFN-γ, contributing to suppression of IFN-γ-mediated epithelial defense in neonatal intestine. Our data demonstrate that XR_001779380 is an important regulator in IFN-γ-mediated gene transcription and age-associated intestinal epithelial antimicrobial defense.
Highlights
Interferon (IFN) signaling is key to mucosal immunity in the gastrointestinal tract, but cellular regulatory elements that determine interferon gamma (IFN-g)-mediated antimicrobial defense in intestinal epithelial cells are not fully understood
We previously demonstrated that a long intergenic noncoding RNAs (ncRNAs), lincRNA-Cox2, one of the most highly induced long noncoding RNA (lncRNA) in macrophages, regulates inflammatory gene transcription in intestinal epithelial cells through modulating ATPdependent chromatin remodeling [10, 11]
Infected IEC4.1 cells demonstrated a significant alteration in lncRNA expression profile
Summary
Interferon (IFN) signaling is key to mucosal immunity in the gastrointestinal tract, but cellular regulatory elements that determine interferon gamma (IFN-g)-mediated antimicrobial defense in intestinal epithelial cells are not fully understood. IMPORTANCE Epithelial cells along the mucosal surface provide the front line of defense against luminal pathogen infection in the gastrointestinal tract These epithelial cells represent an integral component of a highly regulated communication network that can transmit essential signals to cells in the underlying intestinal mucosa that, in turn, serve as targets of mucosal immune mediators. We previously demonstrated that a long intergenic ncRNA, lincRNA-Cox, one of the most highly induced lncRNAs in macrophages, regulates inflammatory gene transcription in intestinal epithelial cells through modulating ATPdependent chromatin remodeling [10, 11]. The key cellular regulatory elements that determine IFN-g-mediated intestinal epithelial anti-Cryptosporidium defense, as well as its association with the high susceptibility of infection in AIDS patients and young children, have not been fully elucidated [12, 13]
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