@article{84752e6697794a5b938b0ce03967b340,
title = "The long noncoding RNA falcor regulates Foxa2 expression to maintain lung epithelial homeostasis and promote regeneration",
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.",
keywords = "Cell adhesion, Cell migration, Foxa2, Lung injury, Transcription factors, lncRNAs",
author = "Swarr, {Daniel T.} and Michael Herriges and Shanru Li and Mike Morley and Sharlene Fernandes and Anusha Sridharan and Su Zhou and Garcia, {Benjamin A.} and Kathleen Stewart and Morrisey, {Edward E.}",
note = "Funding Information: We thank Hitesh Deshmukh and Jerilyn Gray for their help in characterizing the immune cell population seen after airway injury in transgenic animals. We acknowledge the assistance of the Research Flow Cytometry Core and Confocal Imaging Core at Cincinnati Children{\textquoteright}s Hospital Medical Center and the Confocal Imaging Core at the University of Pennsylvania. We are thankful for the generous grant support from the following sources: National Institutes of Health grants R01HL132999 (to E.E.M.), R01H L132349 (to E.E.M.), R01HL122993 (to E.E.M.), 4K12HD043245 (to D.T.S.), 7K08HL130666 (to D.T.S.), and R01GM110174 (to B.A.G.) and a Parker B. Francis Fellowship Award (to D.T.S.). Funding Information: GAGE. ChIP-seq data for H3K4me1, H3K4me3, Pol2, Foxa1, and Foxa2 for the mouse lung and human liver were accessed either directly from the ENCODE Project Web site (http://www .encodeproject.org) or via the University of California at Santa Cruz (UCSC) genome browser (https://genome.ucsc.edu) (ENCODE Project Consortium 2012; Sloan et al. 2016). Human expression data for FALCOR and FOXA2 were obtained for 42 different tissue types from the Genotype-Tissue Expression (GTEx) Project database (The GTEx Consortium 2013). The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute; the National Human Genome Research Institute; the National Heart, Lung, and Blood Institute; the National Institute on Drug Abuse; the National Institute of Mental Health; and the National Institute of Neurological Disorders and Stroke. Version 6 of the GTEx data set was obtained directly from the GTEx portal (https://gtexportal.org/home). Expression levels for FALCOR and FOXA2 were plotted across the nine tissue types expressing FALCOR/FOXA2 using the box plot function of ggplot2() in R (Wickham 2016). Expression levels of FALCOR and FOXA2 in individual human lung samples (n = 321) were plotted, and correlation was assessed using a linear regression model with ggplot2 in R. Genomic interval plots were generated using the UCSC genome browser using either the human GRCh37/ hg19 or mouse GRCm38/mm10 genome builds. The Gene Expression Omnibus accession number for the RNA-seq is GSE126818. Publisher Copyright: {\textcopyright} 2019 Swarr et al.",
year = "2019",
month = jun,
day = "1",
doi = "10.1101/gad.320523.118",
language = "English",
volume = "33",
pages = "656--668",
journal = "Genes and Development",
issn = "0890-9369",
number = "11-12",
}