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Two Crohn's Disease Subtypes Uncovered with Expression, Chromatin Profiling

NEW YORK (GenomeWeb) – Crohn's disease may be subdivided into two subtypes based on gene expression patterns found in gut tissue samples, a new study suggests.

As they reported in the journal Gut today, researchers from the University of North Carolina at Chapel Hill and Cedars-Sinai Medical Center used a combination of RNA sequencing and formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) to profile gene expression patterns and chromatin accessibility in non-inflamed colon tissue from dozens of individuals with or without Crohn's disease.

In the process, the team uncovered two apparent molecular subtypes of Crohn's disease that differed dramatically in both their gene expression and chromatin accessibility patterns. One of these subtypes resembled typical colon tissue, while the other more closely clustered with tissue from the ileum, a portion of the small intestine.

"Although we saw a difference between the Crohn's samples and samples from people without Crohn's, we saw an even greater difference at the molecular level between these two subsets of the Crohn's samples," co-senior author Terrence Furey, an associate professor of genetics and biology at UNC, Chapel Hill, said in a statement.

The symptoms, severity, and response to treatment is highly variable between Crohn's disease cases, Furey and his co-authors explained, often making it difficult to come up with appropriate interventions for those with the inflammatory bowel condition.

"The one-treatment-fits-all approach doesn't seem to be working for Crohn's patients," senior author Shehzad Sheikh, an assistant professor of medicine and genetics at UNC, Chapel Hill, said in a statement. "It's plausible that this is because only a subset of patients has the type of disease that responds to standard therapy, whereas, for the rest of the patients, we're really not hitting the right targets."

To explore that possibility in more detail, the researchers used RNA-seq and FAIRE-seq to assess expression and chromatin accessibility in colon tissue samples from 21 individuals with Crohn's disease and 11 unaffected controls.

From these data, they identified hundreds of genes that were differentially expressed between individuals with Crohn's disease, separating them into two clusters, one exhibiting ileum-related expression profiles and another cluster that more closely resembled colon tissue in the control group.

Likewise, the team detected thousands of apparent differences in chromatin accessibility between the two molecular subtypes of the disease, which were subsequently analyzed alongside histone regulatory marks characterized for the Roadmap Epigenomics Project.

Conversely, when they analyzed previously sequenced ileum tissue samples from 201 untreated, pediatric cases of Crohn's disease and 40 unaffected children, the researchers saw some overlapping expression patterns between ileum samples from individuals without Crohn's disease and a subset of those with it.

A closer look at the pathways that differed between ileum- and colon-like samples from adult and pediatric patients suggests that the subtypes may also differ in their metabolic and immune features, the authors reported.

"Our results suggest that additional testing of patients with [Crohn's disease] for particular molecular signature, especially metabolic pathways, may determine potential therapeutic subgroups," they wrote.