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Peer-reviewedCC BY 4.0Frontiers in Immunology

GART expression is associated with a proliferative and purine-metabolic ISC-like epithelial state in ulcerative colitis

  • Jinchen Chong1,2
  • Haoyu Ding1,2
  • Jiaze Ma1,3
  • Yuan Li1
  • Jie Pan1
  • Yang Li1,4
  • Yugen Chen1,3,5,6
6 affiliations
  1. 1The Affiliated Hospital of Nanjing University of Chinese Medicine
  2. 2No. 1 Clinical Medical College, Nanjing University of Chinese Medicine
  3. 3Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine
  4. 4Endoscopy Center, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)
  5. 5Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine
  6. 6Jiangsu Collaborative Innovation Center of Chinese Medicine in Prevention and Treatment of Tumor, The Affiliated Hospital of Nanjing University of Chinese Medicine
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Abstract

Objective: To characterize the epithelial state associated with GART expression in ulcerative colitis (UC) and determine whether this association reflects a GART-specific program or a broader proliferative and purine-metabolic phenotype.

Methods: Four independent bulk transcriptomic cohorts were analyzed and synthesized by random-effects meta-analysis. Human colonic scRNA-seq datasets (GSE214695 and SCP259) were integrated, with principal comparisons repeated using donor-aware pseudobulk or mixed-effects approaches and adjustment for sequencing depth, gene detection, and cell-cycle covariates. GART detection was defined from raw counts and tested using alternative thresholds. Pseudotime, scTenifoldKnk, CellChat/LIANA, and transcriptional-network analyses were used as exploratory analyses. Spatial transcriptomics (GSE189184), human colonic multiplex immunofluorescence, and acute DSS-induced colitis tissues were used for tissue-level localization.

Results: Across the four bulk cohorts, GART expression showed an overall increase in UC (pooled Hedges’ g = 0.743, 95% CI 0.239–1.248; P = 0.0183). In the single-cell atlas, GART detection localized preferentially to an ISC-like epithelial compartment, although the magnitude of the UC-associated detection difference varied between cohorts. Within UC ISC-like cells, donor-paired pseudobulk analyses identified proliferative and nucleotide-metabolic transcriptional differences associated with GART detection. Across the broader ISC-like epithelial atlas, donor-aware module analyses showed positive associations of GART detection with purine-biosynthesis, DNA-replication, DNA-repair, and mitotic programs, and these associations remained positive within cell-cycle strata. Comparison with other de novo purine-synthesis enzymes did not support a uniquely GART-specific alteration. Exploratory network analyses linked the GART-associated state to proliferative and nucleotide-metabolic programs but did not establish functional dependence. In seven independent spatial donors, the single-cell-derived epithelial program was consistently higher in GART-detected than GART-undetected epithelial regions (mean within-donor difference = 0.0262, 95% CI 0.0140–0.0407; exact P = 0.0156). Human tissue immunofluorescence further showed co-enrichment of GART with OLFM4-positive ISC-like, MYBL2/Ki67-positive proliferative, and MIF/CD74-associated inflammatory regions across the corresponding panel-specific participant sets.

Conclusion: GART identifies a proliferative and purine-metabolic ISC-like epithelial state in UC but is not established as a specific driver of epithelial regeneration. The findings support an association between GART detection, nucleotide-demand programs, proliferative epithelial activity, and the inflammatory tissue context, providing a framework for future direct functional studies.

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Cite

BibTeXRIS
BibTeX
@article{chong2026gart,
  title = {{GART expression is associated with a proliferative and purine-metabolic ISC-like epithelial state in ulcerative colitis}},
  author = {Jinchen Chong and Haoyu Ding and Jiaze Ma and Yuan Li and Jie Pan and Yang Li and Yugen Chen},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1913904},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1913904/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - GART expression is associated with a proliferative and purine-metabolic ISC-like epithelial state in ulcerative colitis
AU  - Jinchen Chong
AU  - Haoyu Ding
AU  - Jiaze Ma
AU  - Yuan Li
AU  - Jie Pan
AU  - Yang Li
AU  - Yugen Chen
PY  - 2026
DA  - 2026/10/05
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1913904
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1913904/full
AB  - Objective: To characterize the epithelial state associated with GART expression in ulcerative colitis (UC) and determine whether this association reflects a GART-specific program or a broader proliferative and purine-metabolic phenotype.  Methods: Four independent bulk transcriptomic cohorts were analyzed and synthesized by random-effects meta-analysis. Human colonic scRNA-seq datasets (GSE214695 and SCP259) were integrated, with principal comparisons repeated using donor-aware pseudobulk or mixed-effects approaches and adjustment for sequencing depth, gene detection, and cell-cycle covariates. GART detection was defined from raw counts and tested using alternative thresholds. Pseudotime, scTenifoldKnk, CellChat/LIANA, and transcriptional-network analyses were used as exploratory analyses. Spatial transcriptomics (GSE189184), human colonic multiplex immunofluorescence, and acute DSS-induced colitis tissues were used for tissue-level localization.  Results: Across the four bulk cohorts, GART expression showed an overall increase in UC (pooled Hedges’ g = 0.743, 95% CI 0.239–1.248; P = 0.0183). In the single-cell atlas, GART detection localized preferentially to an ISC-like epithelial compartment, although the magnitude of the UC-associated detection difference varied between cohorts. Within UC ISC-like cells, donor-paired pseudobulk analyses identified proliferative and nucleotide-metabolic transcriptional differences associated with GART detection. Across the broader ISC-like epithelial atlas, donor-aware module analyses showed positive associations of GART detection with purine-biosynthesis, DNA-replication, DNA-repair, and mitotic programs, and these associations remained positive within cell-cycle strata. Comparison with other de novo purine-synthesis enzymes did not support a uniquely GART-specific alteration. Exploratory network analyses linked the GART-associated state to proliferative and nucleotide-metabolic programs but did not establish functional dependence. In seven independent spatial donors, the single-cell-derived epithelial program was consistently higher in GART-detected than GART-undetected epithelial regions (mean within-donor difference = 0.0262, 95% CI 0.0140–0.0407; exact P = 0.0156). Human tissue immunofluorescence further showed co-enrichment of GART with OLFM4-positive ISC-like, MYBL2/Ki67-positive proliferative, and MIF/CD74-associated inflammatory regions across the corresponding panel-specific participant sets.  Conclusion: GART identifies a proliferative and purine-metabolic ISC-like epithelial state in UC but is not established as a specific driver of epithelial regeneration. The findings support an association between GART detection, nucleotide-demand programs, proliferative epithelial activity, and the inflammatory tissue context, providing a framework for future direct functional studies.
SN  - 1664-3224
ER  -