Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression

Janneke G C Peeters, Stephin J Vervoort, Sander C Tan, Gerdien Mijnheer, Sytze de Roock, Sebastiaan J Vastert, Edward E S Nieuwenhuis, Femke van Wijk, Berent J Prakken, Menno P Creyghton, Paul J Coffer, Michal Mokry, Jorg van Loosdregt

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.

Original languageEnglish
Pages (from-to)1986-96
Number of pages11
JournalCell Reports
Volume12
Issue number12
DOIs
Publication statusPublished - 29 Sep 2015

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