The long noncoding RNA falcor regulates Foxa2 expression to maintain lung epithelial homeostasis and promote regeneration

Daniel T. Swarr, Michael Herriges, Shanru Li, Mike Morley, Sharlene Fernandes, Anusha Sridharan, Su Zhou, Benjamin A. Garcia, Kathleen Stewart, Edward E. Morrisey

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor–Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.

Original languageEnglish
Pages (from-to)656-668
Number of pages13
JournalGenes and Development
Volume33
Issue number11-12
DOIs
StatePublished - Jun 1 2019

Keywords

  • Cell adhesion
  • Cell migration
  • Foxa2
  • Lung injury
  • Transcription factors
  • lncRNAs

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