GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis.

Autor: Sosnovski KE; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Braun T; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Amir A; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Moshel D; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., BenShoshan M; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., VanDussen KL; Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Levhar N; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Abbas-Egbariya H; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Beider K; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Ben-Yishay R; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Asad Ali S; Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan., Moore SR; Department of Pediatrics, University of Virginia, Charlottesville, VA, USA., Kugathasan S; Emory University, Atlanta, GA, USA., Abramovich I; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa, Israel., Glick Saar E; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Weiss B; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Barshack I; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Gottlieb E; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa, Israel., Geiger T; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Ben-Horin S; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel., Ulitsky I; Departments of Biological Regulation and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel., Hyams JS; Connecticut Children's Medical Center, Hartford, CT, USA., Denson LA; Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Haberman Y; Sheba Medical Center, Tel-Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel.; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jazyk: angličtina
Zdroj: Journal of Crohn's & colitis [J Crohns Colitis] 2023 Jun 16; Vol. 17 (6), pp. 960-971.
DOI: 10.1093/ecco-jcc/jjad006
Abstrakt: Background and Aims: Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined.
Methods: Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions.
Results: GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn's disease [CD] ileum and UC rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to a more severe UC form, and to a less favourable UC course. The GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in coeliac disease that is induced in UC, CD and coeliac disease, in contrast to GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with a reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in a reduction of metabolites linked to aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1-deficient cells rescued mitochondrial respiration.
Conclusions: GATA6-AS1 levels are reduced in UC, CD and coeliac disease, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.
(© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje