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Cell-intrinsic aryl hydrocarbon receptor signalling is required for the resolution of injury-induced colonic stem cells

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journal contribution
posted on 11.04.2022, 11:52 authored by 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, Brigitta Stockinger
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.

Funding

Crick (Grant ID: 10159, Grant title: Stockinger FC001159) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Wellcome Trust (Grant ID: 210556/Z/18/Z, Grant title: WT 210556/Z/18/Z)

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