Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells

Kathleen Shah, Muralidhara Rao Maradana, M. Joaquina Delàs, Amina Metidji, Frederike Graelmann, Miriam Llorian, Probir Chakravarty, Ying Li, Mauro Tolaini, Michael Shapiro, Gavin Kelly, Chris Cheshire, Deendyal Bhurta, Sandip B. Bharate and Brigitta Stockinger ()
Additional contact information
Kathleen Shah: The Francis Crick Institute
Muralidhara Rao Maradana: The Francis Crick Institute
M. Joaquina Delàs: The Francis Crick Institute
Amina Metidji: St Jude Children’s Hospital
Frederike Graelmann: University of Bonn
Miriam Llorian: The Francis Crick Institute
Probir Chakravarty: The Francis Crick Institute
Ying Li: The Francis Crick Institute
Mauro Tolaini: The Francis Crick Institute
Michael Shapiro: The Francis Crick Institute
Gavin Kelly: The Francis Crick Institute
Chris Cheshire: The Francis Crick Institute
Deendyal Bhurta: CSIR - Indian Institute of Integrative Medicine
Sandip B. Bharate: CSIR - Indian Institute of Integrative Medicine
Brigitta Stockinger: The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associated Yap/Tead transcriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.

Date: 2022
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DOI: 10.1038/s41467-022-29098-7

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