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

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 be...

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Detalles Bibliográficos
Autores principales: Sosnovski, Katya E, Braun, Tzipi, Amir, Amnon, Moshel, Danielle, BenShoshan, Marina, VanDussen, Kelli L, Levhar, Nina, Abbas-Egbariya, Haya, Beider, Katia, Ben-Yishay, Rakefet, Asad Ali, Syed, Moore, Sean R, Kugathasan, Subra, Abramovich, Ifat, Glick Saar, Efrat, Weiss, Batya, Barshack, Iris, Gottlieb, Eyal, Geiger, Tamar, Ben-Horin, Shomron, Ulitsky, Igor, Hyams, Jeffrey S, Denson, Lee A, Haberman, Yael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Original Articles
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10274303/
https://www.ncbi.nlm.nih.gov/pubmed/36655602
http://dx.doi.org/10.1093/ecco-jcc/jjad006
Descripción
Sumario: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.

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