Genome-wide effect of pulmonary airway epithelial cell–specific Bmal1 deletion

Zhenguang Zhang, Louise Hunter, Gang Wu, Robert Maidstone, Yasutaka Mizoro, Ryan Vonslow, Mark Fife, Thomas Hopwood, Nicola Begley, Ben Saer, Ping Wang, Peter Cunningham, Matthew Baxter, Hannah Durrington, John F. Blaikley, Tracy Hussell, Magnus Rattray, John B. Hogenesch, Julie Gibbs, David W. RayAndrew S.I. Loudon

Research output: Contribution to journalArticlepeer-review


Pulmonary airway epithelial cells (AECs) form a critical interface between host and environment. We investigated the role of the circadian clock using mice bearing targeted deletion of the circadian gene brain and muscle ARNT-like 1 (Bmal1) in AECs. Pulmonary neutrophil infiltration, biomechanical function, and responses to influenza infection were all disrupted. A circadian time-series RNA sequencing study of laser-captured AECs revealed widespread disruption in genes of the core circadian clock and output pathways regulating cell metabolism (lipids and xenobiotics), extracellular matrix, and chemokine signaling, but strikingly also the gain of a novel rhythmic transcriptome in Bmal1-targeted cells. Many of the rhythmic components were replicated in primary AECs cultured in air-liquid interface, indicating significant cell autonomy for control of pulmonary circadian physiology. Finally, we found that metabolic cues dictate phasing of the pulmonary clock and circadian responses to immunologic challenges. Thus, the local circadian clock in AECs is vital in lung health by coordinating major cell processes such as metabolism and immunity.—Zhang, Z. Hunter, L., Wu, G., Maidstone, R., Mizoro, Y., Vonslow, R., Fife, M., Hopwood, T., Begley, N., Saer, B., Wang, P., Cunningham, P., Baxter, M., Durrington, H., Blaikley, J. F., Hussell, T., Rattray, M., Hogenesch, J. B., Gibbs, J., Ray, D. W., Loudon, A. S. I. Genome-wide effect of pulmonary airway epithelial cell-specific Bmal1 deletion. FASEB J. 33, 6226–6238 (2019).
Original languageEnglish
Pages (from-to)6226-6238
Number of pages13
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Issue number5
Early online date22 Feb 2019
Publication statusPublished - 1 May 2019


  • circadian clock
  • airway epithelial cell
  • time serial RNA seq
  • metabolism
  • lung function
  • air liquid interface culture
  • influenza infection
  • food entrainment


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