Bioluminescence imaging of Cyp1a1-luciferase reporter mice demonstrates prolonged activation of the aryl hydrocarbon receptor in the lung

Veland, N.; Gleneadie, H. J.; Brown, K. E.; Sardini, A.; Pombo, J.; Dimond, A.; Burns, V.; Sarkisyan, K.; Schiering, C.; Webster, Z.; Merkenschlager, M.; Fisher, A. G.

doi:10.1101/2023.05.30.542862

bioRxiv · 10.1101/2023.05.30.542862

Bioluminescence imaging of Cyp1a1-luciferase reporter mice demonstrates prolonged activation of the aryl hydrocarbon receptor in the lung

Veland, N.·Gleneadie, H. J.·Brown, K. E.·Sardini, A.·Pombo, J.·Dimond, A.·Burns, V.·Sarkisyan, K.·Schiering, C.·Webster, Z.·Merkenschlager, M.·Fisher, A. G.

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Abstract

Aryl hydrocarbon receptor (AHR) signalling integrates biological processes that sense and respond to environmental, dietary, and metabolic challenges to ensure tissue homeostasis. AHR is a transcription factor that is inactive in the cytosol but upon encounter with ligand translocates to the nucleus and drives the expression of AHR targets, including genes of the cytochrome P4501 family of enzymes such as Cyp1a1. To dynamically visualise AHR activity in vivo, we generated reporter mice in which firefly luciferase (Fluc) was non-disruptively targeted into the endogenous Cyp1a1 locus. Exposure of these animals to FICZ, 3-MC or to dietary I3C induced strong bioluminescence signal and Cyp1a1 expression in many organs including liver, lung and intestine. Longitudinal studies revealed that AHR activity was surprisingly long-lived in the lung, with sustained Cyp1a1 expression evident in discrete populations of cells including columnar epithelia around bronchioles. Our data link diet to lung physiology and also reveal the power of bespoke Cyp1a1-Fluc reporters to longitudinally monitor AHR activity in vivo.

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Veland, N., Gleneadie, H. J., Brown, K. E., Sardini, A., Pombo, J., Dimond, A., Burns, V., Sarkisyan, K., Schiering, C., Webster, Z., Merkenschlager, M., Fisher, A. G.. 2023-05-31. Bioluminescence imaging of Cyp1a1-luciferase reporter mice demonstrates prolonged activation of the aryl hydrocarbon receptor in the lung. https://doi.org/10.1101/2023.05.30.542862

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