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: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

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

14 Scopus citations

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
DOIs	https://doi.org/10.1093/ecco-jcc/jjad006
State	Published - 16 Jun 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation.

Funding

This work was supported by the ERC starting grant [YH, grant No. 758313], the Israel Science Foundation [YH, grant No. 908/15], the I-CORE programme [YH, grant No. 41/11], the Helmsley Charitable Trust, and NIDDK P30 DK078392 [Integrative Morphology and Gene Expression Cores]. PROTECT was supported by the NIDDK 5U01DK095745, RISK was supported by Crohn’s & Colitis Foundation, SEEM by the Bill and Melinda Gates Foundation [OPP1144149 and OPP1138727], and SOURCE is supported by the Helmsley Charitable Trust. The funding sources did not play a role in writing of the manuscript or the decision to submit it for publication, did not play a role in data collection, analysis or interpretation; trial design; patient recruitment; or any aspect pertinent to the study.

Funders	Funder number
I-CORE programme	41/11
SEEM
Bill and Melinda Gates Foundation	OPP1144149, OPP1138727
Leona M. and Harry B. Helmsley Charitable Trust	P30 DK078392, 5U01DK095745
Crohn's and Colitis Foundation
European Commission	758313
Israel Science Foundation	908/15

Keywords

GATA6-AS1 long non-coding RNA
inflammatory bowel disease
mitochondria

UN SDGs

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

Access to Document

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

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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 = "GATA6-AS1 long non-coding RNA, 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 = "16",

doi = "10.1093/ecco-jcc/jjad006",

language = "אנגלית",

volume = "17",

pages = "960--971",

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

issn = "1873-9946",

publisher = "Oxford University Press",

number = "6",

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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, 16.06.2023, 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 - 2023/6/16

Y1 - 2023/6/16

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

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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

Bibliographical note

Funding

Keywords

UN SDGs

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