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Decoding the role of H19 in cholestatic liver injury using snRNA-seq, spatial transcriptomics, and machine
Grayson W Way1, Xixian Jiang1, Hongkun Lu1
1Department of Microbiology and Immunology, Richmond VA Medical Center, Virginia Commonwealth University, 1220 East Broad Street, MMRB-5044, Richmond, VA, 23298-0678, USA.
Cell & Bioscience
|May 29, 2026
Summary
Deleting long non-coding RNA H19 (H19) reduces liver injury in Primary Sclerosing Cholangitis (PSC) models by targeting specific cell states and signaling pathways. This finding offers potential for improving therapies and predicting transplant recurrence.
Area of Science:
- Hepatology and Molecular Biology
- Genomics and Bioinformatics
- Translational Medicine
Background:
- Primary Sclerosing Cholangitis (PSC) is a chronic liver disease with limited treatment options and high transplant recurrence rates.
- Long non-coding RNA H19 (H19) is implicated in PSC progression, but its precise role is unclear.
- Understanding H19's mechanisms is crucial for developing new PSC therapies.
Purpose of the Study:
- To investigate the cellular and molecular impact of H19 deletion in a mouse model of cholestatic liver injury.
- To identify cell-type-specific gene expression changes and signaling pathways affected by H19.
- To validate findings using human datasets and machine learning for translational relevance.
Main Methods:
- Single-nucleus RNA sequencing (snRNAseq) and GeoMx spatial transcriptomics on mouse liver tissues (wild type, H19 knockout, Mdr2 knockout, and double knockout).
- Development and cross-validation of machine learning models using mouse and human (GSE243981) transcriptomic data.
- Analysis of specific cholangiocyte subclusters and SPP1 signaling pathways.
Main Results:
- H19 deletion markedly reduced a disease-associated cholangiocyte subcluster in Mdr2 knockout mice.
- SPP1 signaling dysregulation in cholestatic injury was mitigated by H19 deletion.
- Machine learning models achieved high accuracy (AUC > 0.869) in cross-species validation, identifying conserved cholangiocyte markers.
- Spatial transcriptomics revealed H19 deletion's protective effects were localized to hepatocytes in the periductal niche.
Conclusions:
- H19 deletion ameliorates cholestatic liver injury by suppressing pathogenic cholangiocyte states and normalizing SPP1 signaling.
- The study identified translationally conserved markers for PSC and potential therapeutic targets.
- Machine learning signatures derived from this study show promise for post-transplant analytics and predicting disease recurrence.
