Silencer-enhancer transition dysregulates interleukin-6 in mucosal epithelial cell plasticity

Respiratory viruses, such as Influenza A virus, rhinovirus (RV), respiratory syncytial virus (RSV) and coronavirus, trigger innate inflammation and lung tissue damage in patients of all ages, particularly premature infants and elderly adults. During respiratory viral infection, interleukin-6 (IL-6) plays a pivotal role in promptly and transiently activating and regulating the proper mucosal antiviral immunity to fight and clear the pathogen. However, excessive and persistent IL-6 production may promote virus survival and exacerbation of clinical symptoms. Therefore, the regulatory mechanisms that shape and fine-tune the precise IL-6 response to respiratory viruses needs to be well understood. In order to gain insight into the genome-wide control of gene transcription in mucosal epithelial antiviral response, we applied precision nuclear run-on next generation sequencing (PRO-Seq) to human small airway epithelial cells (hSAECs) infected with RV. In the IL-6 gene locus, we have identified an upstream cis-regulatory element (URE) that resides within an open chromatin domain and encodes noncoding RNAs bidirectionally. Our preliminary data showed that this unannotated URE is a dual-function regulatory element of IL-6 expression, acting as a silencer in normal airway epithelial cells but as an enhancer in epithelial cells that undergo cellular plasticity to develop mesenchymal characteristics as seen in chronic airway remodeling. In this R21 application, we will investigate the hypothesis that the IL-6 URE is an epigenetic silencer of IL-6 expression in mucosal epithelial cells, and that the silencerenhancer transition dysregulates IL-6 expression in response to cellular plasticity. Our project seeks to understand how the functional switch of the IL-6 URE from silencer to enhancer activity associates with IL-6 expression, either through chromatin interactions with IL-6 promoter (chromatin looping) or via functions of its bidirectional non-coding RNAs.

 

Yang, Jun PD/ Pl

Kudlicki, Andrzej Co-Investigator

Zhang, Kangling Co-Investigator