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

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

doi:https://doi.org/10.1093/ecco-jcc/jjad006

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

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-HorinIgor Ulitsky, Jeffrey S. Hyams, Lee A. Denson, Yael Haberman

Tel Aviv University, Weizmann Institute of Science, Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	960-971
Number of pages	12
Journal	Journal of Crohn's and Colitis
Volume	17
Issue number	6
Early online date	19 Jan 2023
DOIs	https://doi.org/10.1093/ecco-jcc/jjad006
State	Published - 1 Jun 2023

Keywords

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

All Science Journal Classification (ASJC) codes

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

https://doi.org/10.1093/ecco-jcc/jjad006

Cite this

Sosnovski, K. E., Braun, T., Amir, A., Moshel, D., Benshoshan, M., Vandussen, K. L., Levhar, N., Abbas-Egbariya, H., Beider, K., Ben-Yishay, R., Asad Ali, S., Moore, S. R., Kugathasan, S., Abramovich, I., Glick Saar, E., Weiss, B., Barshack, I., Gottlieb, E., Geiger, T., ... Haberman, Y. (2023). GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis. Journal of Crohn's and Colitis, 17(6), 960-971. Advance online publication. https://doi.org/10.1093/ecco-jcc/jjad006

@article{63c58e412bc94b9d98ee1eb60502ad0a,

title = "GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative 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-na{\"i}ve 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 = "Caco-2 Cells, Celiac Disease, Colitis, Ulcerative/genetics, Crohn Disease/metabolism, GATA6 Transcription Factor/metabolism, GATA6-AS1 long non-coding RNA, Humans, Inflammation/metabolism, Intestinal Mucosa/metabolism, Mitochondria/metabolism, Rectum, inflammatory bowel disease, mitochondria",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation.",

year = "2023",

month = jun,

day = "1",

doi = "https://doi.org/10.1093/ecco-jcc/jjad006",

language = "الإنجليزيّة",

volume = "17",

pages = "960--971",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Oxford University Press",

number = "6",

}

Sosnovski, KE, Braun, T, Amir, A, Moshel, D, Benshoshan, M, Vandussen, KL, Levhar, N, Abbas-Egbariya, H, Beider, K, Ben-Yishay, R, Asad Ali, S, Moore, SR, Kugathasan, S, Abramovich, I, Glick Saar, E, Weiss, B, Barshack, I, Gottlieb, E, Geiger, T, Ben-Horin, S, Ulitsky, I, Hyams, JS, Denson, LA & Haberman, Y 2023, 'GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis', Journal of Crohn's and Colitis, vol. 17, no. 6, pp. 960-971. https://doi.org/10.1093/ecco-jcc/jjad006

GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis. / Sosnovski, Katya E.; Braun, Tzipi; Amir, Amnon et al.
In: Journal of Crohn's and Colitis, Vol. 17, No. 6, 01.06.2023, p. 960-971.

Research output: Contribution to journal › Article › peer-review

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

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 - Caco-2 Cells

KW - Celiac Disease

KW - Colitis, Ulcerative/genetics

KW - Crohn Disease/metabolism

KW - GATA6 Transcription Factor/metabolism

KW - GATA6-AS1 long non-coding RNA

KW - Humans

KW - Inflammation/metabolism

KW - Intestinal Mucosa/metabolism

KW - Mitochondria/metabolism

KW - Rectum

KW - inflammatory bowel disease

KW - mitochondria

UR - http://www.scopus.com/inward/record.url?scp=85163714872&partnerID=8YFLogxK

U2 - https://doi.org/10.1093/ecco-jcc/jjad006

DO - https://doi.org/10.1093/ecco-jcc/jjad006

M3 - مقالة

C2 - 36655602

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 -

Sosnovski KE, Braun T, Amir A, Moshel D, Benshoshan M, Vandussen KL et al. GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis. Journal of Crohn's and Colitis. 2023 Jun 1;17(6):960-971. Epub 2023 Jan 19. doi: https://doi.org/10.1093/ecco-jcc/jjad006

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

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this