title: Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.
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.
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors.forename: Janneke G C
authors.initials: JG
authors.lastname: Peeters
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Hubrecht Institute and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
authors.forename: Sander C
authors.initials: SC
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Gerdien
authors.initials: G
authors.lastname: Mijnheer
authors.affiliation: 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.
authors.forename: Sytze
authors.initials: S
authors.lastname: de Roock
authors.affiliation: 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.
authors.forename: Sebastiaan J
authors.initials: SJ
authors.lastname: Vastert
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: 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.
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.affiliation: 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.
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
authors.affiliation: Hubrecht Institute and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
authors.forename: Menno P
authors.initials: MP
authors.lastname: Creyghton
authors.affiliation: 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.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: 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.
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity; D001381:Azepines / Q000494:pharmacology*; D001483:Base Sequence; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000187:drug effects; D044127:Epigenesis, Genetic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007156:Immunologic Memory; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D061251:Primary Cell Culture; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001381:Azepines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D018121:Receptors, Cytokine; D014230:Triazoles