Abstract
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.
Highlights
ABBREVIATIONS: airway epithelial cells (AECs), airway epithelial cell; ALI, air-liquid interface; Bronchoalveolar lavage (BAL), bronchoalveolar lavage; BMAL1, brain and muscle ARNT-like 1; CCSP, club cell secretory protein; CLOCK, Circadian Locomotor Output Cycles Kaput; CRY, cryptochrome; CT, circadian time; DE, differentially expressed; KEGG, Kyoto Encyclopedia of Genes and Genomes; LCM, laser-capture microdissection; mTEC, membrane-thermotolerant Escherichia coli; PER, period; pfu, plaque-forming unit; qPCR, quantitative PCR; RNAseq, RNA sequencing; receptor element (RRE), ROR element; WT, wild type; ZT, zeitgeber time
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
We show that Bmal1 plays an important role in a diverse range of cellular functions in AECs, regulating pulmonary neutrophil infiltration, biomechanical function, and influenza infection
Summary
ABBREVIATIONS: AEC, airway epithelial cell; ALI, air-liquid interface; BAL, bronchoalveolar lavage; BMAL1, brain and muscle ARNT-like 1; CCSP, club cell secretory protein; CLOCK, Circadian Locomotor Output Cycles Kaput; CRY, cryptochrome; CT, circadian time; DE, differentially expressed; KEGG, Kyoto Encyclopedia of Genes and Genomes; LCM, laser-capture microdissection; mTEC, membrane-thermotolerant Escherichia coli; PER, period; pfu, plaque-forming unit; qPCR, quantitative PCR; RNAseq, RNA sequencing; RRE, ROR element; WT, wild type; ZT, zeitgeber time. Multiple pulmonary pathologies are linked to the circadian clock
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