Yap/Taz inhibit goblet cell fate to maintain lung epithelial homeostasis
Julia Hicks-Berthet,
Boting Ning,
Anthony Federico,
Andrew Tilston-Lunel,
Adeline Matschulat,
Xingbin Ai,
Marc E. Lenburg,
Jennifer Beane,
Stefano Monti,
Xaralabos Varelas
Affiliations
Julia Hicks-Berthet
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Boting Ning
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA 02118, USA
Anthony Federico
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA 02118, USA; Bioinformatics Program, Boston University, Boston, MA 02215, USA
Andrew Tilston-Lunel
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Adeline Matschulat
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Xingbin Ai
Division of Neonatology and Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA
Marc E. Lenburg
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA 02118, USA
Jennifer Beane
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA 02118, USA
Stefano Monti
Department of Medicine, Computational Biomedicine Section, Boston University School of Medicine, Boston, MA 02118, USA; Bioinformatics Program, Boston University, Boston, MA 02215, USA
Xaralabos Varelas
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA; Corresponding author
Summary: Proper lung function relies on the precise balance of specialized epithelial cells that coordinate to maintain homeostasis. Herein, we describe essential roles for the transcriptional regulators YAP/TAZ in maintaining lung epithelial homeostasis, reporting that conditional deletion of Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects, including alveolar disorganization and the development of airway mucin hypersecretion. Through in vivo lineage tracing and in vitro molecular experiments, we reveal that reduced YAP/TAZ activity promotes intrinsic goblet transdifferentiation of secretory airway epithelial cells. Global gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses suggest that YAP/TAZ act cooperatively with TEA domain (TEAD) transcription factors and the NuRD complex to suppress the goblet cell fate program, directly repressing the SPDEF gene. Collectively, our study identifies YAP/TAZ as critical factors in lung epithelial homeostasis and offers molecular insight into the mechanisms promoting goblet cell differentiation, which is a hallmark of many lung diseases.
