TY - JOUR
T1 - GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis
AU - Sosnovski, Katya E.
AU - Braun, Tzipi
AU - Amir, Amnon
AU - Moshel, Danielle
AU - Benshoshan, Marina
AU - Vandussen, Kelli L.
AU - Levhar, Nina
AU - Abbas-Egbariya, Haya
AU - Beider, Katia
AU - Ben-Yishay, Rakefet
AU - Asad Ali, Syed
AU - Moore, Sean R.
AU - Kugathasan, Subra
AU - Abramovich, Ifat
AU - Glick Saar, Efrat
AU - Weiss, Batya
AU - Barshack, Iris
AU - Gottlieb, Eyal
AU - Geiger, Tamar
AU - Ben-Horin, Shomron
AU - Ulitsky, Igor
AU - Hyams, Jeffrey S.
AU - Denson, Lee A.
AU - Haberman, Yael
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - GATA6-AS1 long non-coding RNA
KW - inflammatory bowel disease
KW - mitochondria
UR - http://www.scopus.com/inward/record.url?scp=85163714872&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjad006
DO - 10.1093/ecco-jcc/jjad006
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C2 - 36655602
AN - SCOPUS:85163714872
SN - 1873-9946
VL - 17
SP - 960
EP - 971
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 6
ER -