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Molecular phenotypes in early gallbladder and liver disease in the CFTR-/- sheep highlight aspects of CF-relevant hepatobiliary disease

ABSTRACT: The initiating cellular events in cystic fibrosis (CF) hepatobiliary disease are not well characterized, in part due to lack of accessibility of primary tissues. However, enhanced longevity due to highly effective modulator therapies has generated renewed interest in key aspects of liver and gallbladder disease, and how these might be treated in people with CF (pwCF). To extend the CF hepatobiliary knowledgebase, we performed a transcriptomic analysis of liver and gallbladder development in the wild type (WT) and CFTR-/- sheep. Bulk RNA was extracted from each tissue at specific timepoints through gestation (from 50 days to term) and used for RNA-seq. Differentially expressed genes between the timepoints within each genotype and between WT and CFTR-/- sheep at each timepoint were identified, and then used in gene ontology process enrichment analysis to reveal altered biological processes. We find that at the molecular level, the gallbladder in the CFTR-/- animals is both structurally and functionally compromised by mid-gestation, consistent with the observed microgallbladder phenotype. In the liver, many aspects of differentiation are apparently well-established early in gestation. However, we find functional immaturity in the CFTR-/- liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in WT liver. We also show that the regulatory mechanisms for the CFTR gene in ovine gallbladder cells are highly conserved with those elucidated at the human CFTR locus, further enhancing the relevance of these data to advance understanding of hepatobiliary disease in pwCF.

ORGANISM(S): Ovis aries

PROVIDER: GSE306255 | GEO | 2026/04/13

REPOSITORIES: GEO

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