Healthy Airway Development and Repair Depends on a Critical Feedback Loop

Published June 2019 | Genes & Development

A healthy lung depends on precise control of gene expression, from fetal development through adulthood. Researchers at Cincinnati Children’s have identified a new and important mechanism by which key transcription factors are controlled in the lung.

While many scientists have recognized the importance of transcription factors (TFs) in regulating gene expression, less is known about the regulatory relationship between TFs and long noncoding RNAs (lncRNAs).

This study shows that an lncRNA called Falcor functions within a feedback loop to control expression of the gene Foxa2. Disrupting this feedback loop in mice after injury to the airway epithelium impaired normal repair and regeneration of the lung and resulted in chronic inflammation and goblet cell metaplasia.

In the airway, this study shows that disrupting the Falcor–Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic airway inflammation and goblet cell metaplasia. While a certain number of goblet cells are normally present in the human airway, an increase in these mucous producing cells, combined with inflammation, is often seen in lung disease.

Finding and characterizing this feedback loop required a team of researchers from Cincinnati Children’s, Boston University and the University of Pennsylvania led by first author Daniel Swarr, MD, a neonatologist and geneticist with the Perinatal Institute.

Their findings may have important implications for lung diseases ranging from asthma to cancer.

“This is particularly relevant because most human diseases do not result from the complete loss of gene function or complete lack of cell lineage specification during development,” Swarr and colleagues say. “Instead, subtle derangements in gene expression in the context of environmental exposures or repetitive injuries is the norm.”