Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet.

Autor: Meyenberg M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria.; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, 1030, Vienna, Austria., Hakobyan A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, 1030, Vienna, Austria., Papac-Milicevic N; Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria., Göderle L; Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria., Langner FL; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.; Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090, Vienna, Austria., Markovic M; Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria., Lee JH; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, 1030, Vienna, Austria.; Center for Genome Engineering, Institute for Basic Science, 55, Expo-Ro, Yuseong-Gu, Daejeon, 34126, Republic of Korea., Koo BK; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, 1030, Vienna, Austria.; Center for Genome Engineering, Institute for Basic Science, 55, Expo-Ro, Yuseong-Gu, Daejeon, 34126, Republic of Korea., Busslinger GA; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.; Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090, Vienna, Austria., da Silva IT; Laboratory of Computational Biology and Bioinformatics, A.C. Camargo Cancer Center, São Paulo, 01508-010, Brazil., Binder CJ; Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria., Menche J; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria. joerg.menche@univie.ac.at.; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, 1030, Vienna, Austria. joerg.menche@univie.ac.at.; Faculty of Mathematics, University of Vienna, 1090, Vienna, Austria. joerg.menche@univie.ac.at., Loizou JI; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria. joanna_loizou@hotmail.com.; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria. joanna_loizou@hotmail.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Aug 26; Vol. 13 (1), pp. 13964. Date of Electronic Publication: 2023 Aug 26.
DOI: 10.1038/s41598-023-41123-3
Abstrakt: Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje