Final Report, ECCO Grant for Sudipto Das

Sudipto Das, ECCO Grant Awardee

Role of DNA methYlation and geNe expression alterations in development of eArly-onset priMary sclerosIng cholangitis in ulCerative colitis – DYNAMIC

Sudipto Das
© Sudipto Das

Background & aim of research

Primary Sclerosing Cholangitis (PSC) is a progressive choleostatic disease and up to 80% of patients also have Ulcerative Colitis (PSC-UC). This presents a clinical challenge owing to the diagnostic difficulty and the increased risk for development of cancer. The aim of this study was to identify the transcriptomic and epigenetic alterations regulating the phenotype of this disease.

Methodology used in the research

We applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies from three groups of FFPE-derived treatment-naïve children at diagnosis from the DOCHAS study [UC (n=10), PSC-UC (n=10) and healthy controls (n=10)]. Similarly, we applied these approaches to inflamed mucosal biopsies derived from adult UC (n=36) and PSC-UC (n=23) patients.

Main findings/results of the research

Differential gene expression between paediatric treatment-naïve UC and PSC-UC identified disease-associated genes that were either up- or down-regulated in UC or PSC relative to controls. Furthermore, expression of these genes was regulated by master transcriptional regulators (NLRP3, DLL1) and transcription factors (FOXO1, RELA, HSF1).

Importantly, gene expression comparison between UC and PSC-UC revealed nine up- and five down-regulated genes in PSC-UC patients. Notably, APOB, NLRP3 and PNCK, identified as upregulated in the PSC-UC patients, are also significantly up-regulated in gastrointestinal (GI) cancers.

Differential methylation analysis between healthy control biopsies vs PSC-UC and UC demonstrated >1000 differentially methylated regions (DMRs), with a large proportion of these DMRs enriched in enhancer regions. Intriguingly, we did not identify any differences in gene expression between adult UC and PSC-UC patients. However, differential methylation analysis is currently ongoing for these adult patient cohorts.

Conclusions and perceived impact of the findings

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 paediatric patients, some of which are associated with GI cancers. Their potential utility as predictive biomarkers of PSC development in UC or dysplasia risk in PSC-UC warrants further validation through larger patient cohorts.

Posted in ECCO News, SciCom, Committee News, Volume 18, Issue 3, Fellowships & Grants Synopsis Reports