The University of Southampton
University of Southampton Institutional Repository

Ileal transcriptomic analysis in paediatric Crohn's disease reveals IL17- and NOD-signalling expression signatures in treatment-naïve patients and identifies epithelial cells driving differentially expressed genes

Ileal transcriptomic analysis in paediatric Crohn's disease reveals IL17- and NOD-signalling expression signatures in treatment-naïve patients and identifies epithelial cells driving differentially expressed genes
Ileal transcriptomic analysis in paediatric Crohn's disease reveals IL17- and NOD-signalling expression signatures in treatment-naïve patients and identifies epithelial cells driving differentially expressed genes
Background/Aims
Crohn’s disease (CD) arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD.

Methods
- We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted-gene-co-expression-network-analysis (WGCNA) was performed and differentially expressed genes (DEGs) were determined. We integrated clinical data to determine co-expression modules associated with outcomes.

Results
- Twenty-seven treatment-naive CD (TN-CD), 26 established-CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established-CD, or controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes including S100A12 and the calprotectin subunit S100A9 were significantly upregulated in TN CD compared to controls (p=2.61x10 -15 and p=9.13x10 -14, respectively) and established-CD (both p=0.0055). Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene-signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse (correlation-coefficient-0.36, p=0.07).Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene-expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells.

Conclusion
- Ileal tissue from treatment naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.
1873-9946
Ashton, James John
1c0bfa29-794c-4fd5-93e0-6769e6037d72
Boukas, Konstantinos
4cbff114-7077-45ad-95e7-2c6a03761380
Davies, James David
a93b4fc9-80a2-4620-ada6-c12f05c5ee38
Stafford, Imogen Sian
50987dc1-3772-408f-9093-9124f3d6b2cd
Vallejo, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Coelho, Tracy Antonio Francisco
83bbf944-8998-4f1f-ae32-ad2315bb5f8f
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Vadgama, Bhumita
3a9f04f7-2ae2-4c42-aa91-33a4bb3cea12
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Beattie, R. Mark
55d81c7b-08c9-4f42-b6d3-245869badb71
Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Ashton, James John
1c0bfa29-794c-4fd5-93e0-6769e6037d72
Boukas, Konstantinos
4cbff114-7077-45ad-95e7-2c6a03761380
Davies, James David
a93b4fc9-80a2-4620-ada6-c12f05c5ee38
Stafford, Imogen Sian
50987dc1-3772-408f-9093-9124f3d6b2cd
Vallejo, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Coelho, Tracy Antonio Francisco
83bbf944-8998-4f1f-ae32-ad2315bb5f8f
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Vadgama, Bhumita
3a9f04f7-2ae2-4c42-aa91-33a4bb3cea12
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Beattie, R. Mark
55d81c7b-08c9-4f42-b6d3-245869badb71
Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Ashton, James John, Boukas, Konstantinos, Davies, James David, Stafford, Imogen Sian, Vallejo, Andres, Haggarty, Rachel, Coelho, Tracy Antonio Francisco, Batra, Akshay, Afzal, Nadeem A., Vadgama, Bhumita, Williams, Anthony, Beattie, R. Mark, Polak, Marta and Ennis, Sarah (2020) Ileal transcriptomic analysis in paediatric Crohn's disease reveals IL17- and NOD-signalling expression signatures in treatment-naïve patients and identifies epithelial cells driving differentially expressed genes. Journal of Crohn's and Colitis. (doi:10.1093/ecco-jcc/jjaa236).

Record type: Article

Abstract

Background/Aims
Crohn’s disease (CD) arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD.

Methods
- We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted-gene-co-expression-network-analysis (WGCNA) was performed and differentially expressed genes (DEGs) were determined. We integrated clinical data to determine co-expression modules associated with outcomes.

Results
- Twenty-seven treatment-naive CD (TN-CD), 26 established-CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established-CD, or controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes including S100A12 and the calprotectin subunit S100A9 were significantly upregulated in TN CD compared to controls (p=2.61x10 -15 and p=9.13x10 -14, respectively) and established-CD (both p=0.0055). Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene-signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse (correlation-coefficient-0.36, p=0.07).Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene-expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells.

Conclusion
- Ileal tissue from treatment naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.

Text
Untracked_27_10_20_Targeted transcriptomic analysis in paediatric CD - Accepted Manuscript
Restricted to Repository staff only until 9 November 2021.
Request a copy

More information

Accepted/In Press date: 9 November 2020
e-pub ahead of print date: 24 November 2020

Identifiers

Local EPrints ID: 445052
URI: http://eprints.soton.ac.uk/id/eprint/445052
ISSN: 1873-9946
PURE UUID: 939aab9c-4bca-440f-8ab5-ca078304d3fa
ORCID for Andres Vallejo: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 18 Nov 2020 17:31
Last modified: 23 Jul 2021 01:49

Export record

Altmetrics

Contributors

Author: James John Ashton
Author: Konstantinos Boukas
Author: James David Davies
Author: Imogen Sian Stafford
Author: Andres Vallejo ORCID iD
Author: Rachel Haggarty
Author: Tracy Antonio Francisco Coelho
Author: Akshay Batra
Author: Nadeem A. Afzal
Author: Bhumita Vadgama
Author: R. Mark Beattie
Author: Marta Polak
Author: Sarah Ennis ORCID iD

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×