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Multiomic Sequencing Reveals Distinctive Gene Expression and Epigenetic Alterations Associated With Primary
Alejandra Rodriguez-Sosa1, Ololade Lawal1, Ciaran McDonnell1
1Epigenetics of Gastrointestinal Diseases Research Group, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Background And Aims:
Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease with up to 80% of patients also suffering from ulcerative colitis (PSC-UC). The difficulty in the diagnosis along with the increased risk for developing cancer represents a clinical challenge. Furthermore, the precise molecular factors regulating the phenotype of this disease subtype remain unknown.
Methods:
We applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies from 3 groups of treatment-naïve children at diagnosis from the Determinants and Outcomes in CHildren and AdolescentS study: UC (n = 10), PSC-UC (n = 10), and healthy controls (n = 10).
Results:
Differential gene expression between UC and PSC-UC showed significantly higher gene expression changes in PSC-UC patients when compared to UC. Specifically, expression of these genes was regulated by master transcriptional regulators (NLRP3, DLL1) and transcription factors (RELA, Myogenin, and FOXO1), which are shown to regulate expression of inflammatory response and immune-associated genes in PSC-UC patients exclusively. Differential methylation analysis between PSC-UC and UC demonstrated >2000 differentially methylated regions with a large proportion of them enriched in gene promoter and enhancer regions. We further show no difference in epigenetic age between PSC-UC and UC. Finally, we identify KLHL17 as hypomethylated and upregulated in PSC-UC patients.
Conclusion:
Our study, for the first time, identifies distinct gene expression and DNA methylation alterations that differentiate UC from PSC-UC at diagnosis in treatment-naïve pediatric patients. We show the gene expression differences observed between PSC-UC and UC are modulated by intricate molecular mechanisms involving master transcriptional regulator-mediated signaling through transcription factors. These findings suggest the potential utility of these molecular markers as predictive biomarkers for PSC development in UC at an early stage of development. Further validation in larger patient cohorts is warranted.
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