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

Authors

Katya E Sosnovski
Tzipi Braun
Amnon Amir
Danielle Moshel
Marina BenShoshan
Kelli L VanDussen
Nina Levhar
Haya Abbas-Egbariya
Katia Beider
Rakefet Ben-Yishay
Syed Asad Ali
Sean R Moore
Subra Kugathasan
Ifat Abramovich
Efrat Glick Saar
Batya Weiss
Iris Barshack
Eyal Gottlieb
Tamar Geiger
Shomron Ben-Horin
Igor Ulitsky
Jeffrey S Hyams
Lee A Denson
Yael Haberman

Publication Date

6-16-2023

Journal

Journal of Crohn's and Colitis

Abstract

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.

Keywords

Humans, Colitis, Ulcerative, Caco-2 Cells, Celiac Disease, Intestinal Mucosa, Crohn Disease, Rectum, Inflammation, Mitochondria, GATA6 Transcription Factor, GATA6-AS1 long non-coding RNA, mitochondria, inflammatory bowel disease

Comments

Supplementary Materials

PMID: 36655602