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EHF is essential for epidermal and colonic epithelial homeostasis and suppresses Apc-initiated colonic tumorigenesis

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2021

bioRxiv. 2021 Mar 02. doi: https://doi.org/10.1101/2021.03.01.433470

EHF is essential for epidermal and colonic epithelial homeostasis and suppresses Apc-initiated colonic tumorigenesis

Camilla M. Reehorst, Rebecca Nightingale, Ian Y. Luk, Laura Jenkins, Frank Koentgen, David S. Williams, Charbel Darido, Fiona Tan, Holly Anderton, Michael Chopin, Kael Schoffer, Moritz F. Eissmann, Michael Buchert, Dmitri Mouradov, Oliver M Sieber, Matthias Ernst, Amardeep S. Dhillon, John M. Mariadason

Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia. Ozgene, Perth, Western Australia. Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Walter and Eliza Hall Institute, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia. Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.

Service type: Knockout mice

Abstract

Background: Ets homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) transcription factors. EHF is specifically expressed in epithelial tissues, however its role in development and epithelial homeostasis is largely uncharacterized. Methods: We generated a novel mouse strain in which the Ets DNA binding domain (exon 8) of Ehf was flanked by loxP sites (EhfLox/Lox). To inactivate Ehf in the whole body, EhfLox/Lox mice were crossed to CMVCre mice, which were then bred out to generate germline Ehf null (Ehf−/−) mice. To inactivate Ehf specifically in the intestinal epithelium, EhfLox/Lox mice were bred to tamoxifen-inducible VillinCre-ERT2 mice. EhfLox/Lox mice were also crossed to tamoxifen-inducible Cdx2CreERT2; ApcLox/+ mice to determine the impact of Ehf deletion on Apc-initiated colon cancer development. Results: Transcripts encoding the Ets binding domain of EHF were effectively deleted in all tissues in Ehf−/− mice. Ehf−/− mice were born at the expected Mendelian ratio, but showed reduced body weight gain and developed a series of pathologies during their lifespan that led the majority of Ehf−/− mice to reach an ethical endpoint within one year of age. Most prominent of these were the development of papillomas in the chin, and abscesses in the preputial glands (males) or vulvae (females) which showed evidence of Staphylococcus and Proteus infection. Consistent with the development of papillomas, the epidermis of Ehf−/− mice showed evidence of mild hyperplasia. A subset of Ehf−/− mice also developed cataracts and corneal ulcers. EHF is highly expressed in the colonic epithelium and Ehf−/− mice displayed increased susceptibility to dextran sodium sulphate-induced colitis. This phenotype was confirmed in intestinal-specific Ehf knockout mice, and histopathological analyses revealed reduced numbers of goblet cells and extensive transcriptional reprogramming in the colonic epithelium. Finally, colon-specific deletion of Ehf enhanced Apc-initiated adenoma development, unveiling a novel, tumour suppressive role for EHF in colorectal cancer. Conclusion: The Ets DNA-binding domain of EHF is essential for post-natal homeostasis of the epidermis and colonic epithelium, and functions as a tumour suppressor in the colon.

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