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Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.

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

Author information

1
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
2
Hubrecht Institute and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
3
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands; Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
4
Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
5
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
6
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands; Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands. Electronic address: j.vanloosdregt@umcutrecht.nl.

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.

PMID:
26387944
DOI:
10.1016/j.celrep.2015.08.046
[Indexed for MEDLINE]
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