Dataset Information

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

ABSTRACT:

Background and aims

Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.

Methods

We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.

Results

Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended.

Conclusion

Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.

SUBMITTER: Argmann C

PROVIDER: S-EPMC8640960 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

Argmann Carmen C Tokuyama Minami M Ungaro Ryan C RC Huang Ruiqi R Hou Ruixue R Gurunathan Sakteesh S Kosoy Roman R Di'Narzo Antonio A Wang Wenhui W Losic Bojan B Irizar Haritz H Peters Lauren L Stojmirovic Aleksandar A Wei Gabrielle G Comella Phillip H PH Curran Mark M Brodmerkel Carrie C Friedman Joshua R JR Hao Ke K Schadt Eric E EE Zhu Jun J Cho Judy J Harpaz Noam N Dubinsky Marla C MC Sands Bruce E BE Kasarskis Andrew A Mehandru Saurabh S Colombel Jean-Frederic JF Suárez-Fariñas Mayte M

Gastroenterology 20210902 6

<h4>Background and aims</h4>Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.<h4>Methods</h4>We performed RNA sequence ...[more]

PMID: 34480882

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Project description:Dextran sodium sulfate (DSS)-induced colitis is widely used to study pathological mechanisms and potential treatments of inflammatory bowel disease. Because temporal changes in genome expression profiles remain unknown in this model, we performed whole genome expression profile analysis during the development of DSS colitis in comparison with ulcerative colitis (UC) specimens to identify novel and common responses during disease. Colon tissue from DSS-treated mice was collected at days 0, 2, 4, and 6. Half of each specimen was used for histopathological analysis and half for Affymetrix whole genome expression profiling and qRT-PCR validation. Genesifter and Ingenuity software analysis was used to identify differentially expressed genes and perform interactive network analysis. Identified DSS-associated genes in mice were also compared with UC patient data. We identified 1,609 genes that were significantly altered during DSS colitis; the majority were functionally related to inflammation, angiogenesis, metabolism, biological adhesion, cellular growth and proliferation, and cell-to-cell signaling responses. Five hundred and one genes were progressively upregulated, while one hundred seventy-three genes were progressively downregulated. Changes in gene expression were validated in a subset of 33 genes by qRT-PCR, with r(2) = 0.925. Ingenuity gene interaction network analysis revealed novel relationships among antigen presentation, cell morphology, and other biological functions in the DSS mouse. Finally, DSS colitis gene array data were compared with UC patient array data: 152 genes were similarly upregulated, and 22 genes were downregulated. Temporal genomewide expression profile analysis of DSS-induced colitis revealed novel associations with various immune responses and tissue remodeling events such as angiogenesis similar to those in UC patients. This study provides a comprehensive view of DSS colitis changes in colon gene expression and identifies common molecules with clinical specimens that are interesting targets for further investigation.

Dataset Information

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

Background and aims

Methods

Results

Conclusion

Publications

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

Similar Datasets

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