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Peer-reviewedCC BY-NC-NDBMC gastroenterology

Epigenetic regulation of INPP5D and its downstream molecular network in autoimmune pancreatitis.

  • Takeshi Uehara1
  • Mai Iwaya2
  • Shiho Asaka2,3
  • Tomoyuki Nakajima2
  • Shotaro Komamura2
  • Hiroshi Sawaguchi4
  • Shunsuke Imamura4
  • Akira Nakamura4
  • Shinsuke Sugenoya5
  • Akira Shimizu5
  • Hiroyoshi Ota2,6
6 affiliations
  1. 1Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan. [email protected].
  2. 2Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
  3. 3Department of Laboratory Medicine, Nagano Children's Hospital, Azumino, Japan.
  4. 4Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
  5. 5Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
  6. 6Department of Biomedical Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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Abstract

Aims

Autoimmune pancreatitis (AIP) is a representative manifestation of IgG4-related disease characterized by lymphoplasmacytic inflammation and storiform fibrosis. Although epigenetic dysregulation has been implicated in autoimmune diseases, its contribution to the pathogenesis of AIP remains unclear.Methods and results

Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC array in tissues affected by AIP and obstructive pancreatitis (OP). Differentially methylated regions (DMRs) were identified and subjected to pathway enrichment analysis. Among the significantly enriched gene sets, GNF2_INPP5D showed the strongest enrichment and was selected for further investigation. INPP5D promoter methylation was analyzed, and its protein expression was evaluated by immunohistochemistry. Single-cell RNA sequencing (scRNA-seq) was performed to identify the cells expressing INPP5D. Pathway enrichment analysis showed significant enrichment of the INPP5D-associated immune-regulatory network in AIP. Promoter-associated CpG probes within the INPP5D locus showed predominant hypomethylation in AIP compared with the findings in OP (adjusted p < 0.05). In contrast, immunohistochemistry demonstrated reduced INPP5D expression in spindle-shaped stromal macrophage/histiocyte-lineage cells in AIP tissues. scRNA-seq analysis identified INPP5D expression predominantly in C1QC-positive macrophages and lymphocytes.Conclusions

AIP is characterized by epigenetic remodeling of the INPP5D-associated immune-regulatory network accompanied by reduced INPP5D expression in stromal macrophage-lineage cells. These findings provide evidence for an association between altered INPP5D-related epigenetic regulation and the characteristic fibro-inflammatory microenvironment of AIP. INPP5D may represent a candidate biomarker and a potential therapeutic target in IgG4-related disease.

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Cite

BibTeXRIS
BibTeX
@article{uehara2026epigenetic,
  title = {{Epigenetic regulation of INPP5D and its downstream molecular network in autoimmune pancreatitis.}},
  author = {Takeshi Uehara and Mai Iwaya and Shiho Asaka and Tomoyuki Nakajima and Shotaro Komamura and Hiroshi Sawaguchi and Shunsuke Imamura and Akira Nakamura and Shinsuke Sugenoya and Akira Shimizu and Hiroyoshi Ota},
  journal = {BMC gastroenterology},
  year = {2026},
  month = jul,
  doi = {10.1186/s12876-026-05170-0},
  url = {https://europepmc.org/article/MED/42902176},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Epigenetic regulation of INPP5D and its downstream molecular network in autoimmune pancreatitis.
AU  - Takeshi Uehara
AU  - Mai Iwaya
AU  - Shiho Asaka
AU  - Tomoyuki Nakajima
AU  - Shotaro Komamura
AU  - Hiroshi Sawaguchi
AU  - Shunsuke Imamura
AU  - Akira Nakamura
AU  - Shinsuke Sugenoya
AU  - Akira Shimizu
AU  - Hiroyoshi Ota
PY  - 2026
DA  - 2026/07/01
JO  - BMC gastroenterology
DO  - 10.1186/s12876-026-05170-0
UR  - https://europepmc.org/article/MED/42902176
AB  - Aims  Autoimmune pancreatitis (AIP) is a representative manifestation of IgG4-related disease characterized by lymphoplasmacytic inflammation and storiform fibrosis. Although epigenetic dysregulation has been implicated in autoimmune diseases, its contribution to the pathogenesis of AIP remains unclear.Methods and results  Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC array in tissues affected by AIP and obstructive pancreatitis (OP). Differentially methylated regions (DMRs) were identified and subjected to pathway enrichment analysis. Among the significantly enriched gene sets, GNF2_INPP5D showed the strongest enrichment and was selected for further investigation. INPP5D promoter methylation was analyzed, and its protein expression was evaluated by immunohistochemistry. Single-cell RNA sequencing (scRNA-seq) was performed to identify the cells expressing INPP5D. Pathway enrichment analysis showed significant enrichment of the INPP5D-associated immune-regulatory network in AIP. Promoter-associated CpG probes within the INPP5D locus showed predominant hypomethylation in AIP compared with the findings in OP (adjusted p < 0.05). In contrast, immunohistochemistry demonstrated reduced INPP5D expression in spindle-shaped stromal macrophage/histiocyte-lineage cells in AIP tissues. scRNA-seq analysis identified INPP5D expression predominantly in C1QC-positive macrophages and lymphocytes.Conclusions  AIP is characterized by epigenetic remodeling of the INPP5D-associated immune-regulatory network accompanied by reduced INPP5D expression in stromal macrophage-lineage cells. These findings provide evidence for an association between altered INPP5D-related epigenetic regulation and the characteristic fibro-inflammatory microenvironment of AIP. INPP5D may represent a candidate biomarker and a potential therapeutic target in IgG4-related disease.
SN  - 1471-230X
ER  -