INTEGRATED LIVER TRANSCRIPTOME AND ALTERNATIVE-SPLICING ANALYSIS DEFINES CANDIDATE METABOLIC-INFLAMMATORY AS-DEG REMODELING IN OBSTRUCTIVE JAUNDICE
Keywords:
Obstructive jaundice, Bile duct ligation, RNA-seq, Alternative splicing, Intron retention, AS-DEG, Intestinal barrier, CholestasisAbstract
Background: Obstructive jaundice is associated with cholestatic liver injury and intestinal barrier dysfunction, but the hepatic transcriptional and post-transcriptional programs linking these processes remain incompletely defined. Methods: Human intestinal mucosal hematoxylin and eosin staining and qRT-PCR were integrated with liver RNA sequencing from a mouse bile duct ligation (BDL) model. Differentially expressed genes (DEGs), differential alternative-splicing (AS) events, AS-DEG overlap genes, functional enrichment, module activity, RNA-binding/splicing-regulatory factors, and candidate-gene networks were analyzed. Results: BDL induced marked cholestatic liver injury, with increased TBIL, ALT and ALP, and increased plasma diamine oxidase, indicating intestinal barrier-related disturbance. Human intestinal mucosa showed epithelial injury, and qRT-PCR showed significantly higher YWHAG expression and an upward trend of STAT3 in obstructive jaundice samples. RNA-seq of 10 liver samples generated 129.11 Gb clean bases with Q30 values above 97.16%. BDL liver contained 4,718 DEGs and 1,695 differential AS events, with intron retention as the dominant AS type. Integration of expression and splicing identified 340 AS-DEG overlap genes enriched in lipid/xenobiotic metabolism, inflammation and chemotaxis, redox/mitochondrial metabolism, and adhesion/extracellular-matrix remodeling. Ddx28, Rbm3 and Celf4 were upregulated and inversely correlated with the sample-level AS index. Multi-evidence prioritization highlighted Cyp2a22, Ugt1a9, Clcf1, Lifr, Cybb and related candidates. Conclusions: Obstructive jaundice was associated with coordinated hepatic expression and alternative-splicing remodeling that converged on metabolic-inflammatory injury programs and was supported by intestinal mucosal phenotypic evidence. These findings define a hypothesis-generating candidate framework that requires independent isoform-level and functional validation.References
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