ANP32E, a protein involved in steroid-refractoriness in ulcerative colitis, identified by a systems biology approach.

Background and aims: Steroid-refractoriness is a common and unpredictable phenomenon in ulcerative colitis (UC), but there are no conclusive studies on the molecular functions involved. We aimed to assess in depth the mechanism of action related to steroid failure by integrating transcriptomic data from UC patients, and updated molecular data on UC and glucocorticoids.

Methods: miRNA and mRNA expression were evaluated by sequencing and microarrays, respectively, from rectal biopsies of patients with moderately-to-severe active UC, obtained before and on the 3rd day of steroid treatment. The differential results were integrated into the mathematical models generated by Systems Biology.

Results: This computational approach identified 18 proteins that stand out either by being associated to the mechanism of action or by providing a major capacity to classify the patients according to steroid response. Their biologicals functions have been linked with inflammation, glucocorticoid-induced transcription and angiogenesis. All the selected proteins but ANP32E (a chaperone which has been linked to the exchange of H2A.z histone and promotes glucocorticoid receptor-induced transcription) had previously been related to UC and/or glucocorticoid-induced biological actions. Western blot and immunofluorescence assays confirmed the implication of this chaperone in steroid failure in patients with active UC.

Conclusions: A biology systems approach allowed to identify a comprehensive mechanism of action of steroid-refractoriness, highlighting the key role of steroid-induced transcription and the potential implication of ANP32E in this phenomenon.