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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Juvenile / drug therapy*
  • Arthritis, Juvenile / genetics
  • Arthritis, Juvenile / metabolism
  • Arthritis, Juvenile / pathology
  • Autoimmunity
  • Azepines / pharmacology*
  • Base Sequence
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Enhancer Elements, Genetic / drug effects
  • Epigenesis, Genetic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunologic Memory
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Molecular Sequence Data
  • Primary Cell Culture
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Signal Transduction
  • Synovial Fluid / cytology
  • Synovial Fluid / drug effects
  • Synovial Fluid / metabolism
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Triazoles / pharmacology*

Substances

  • (+)-JQ1 compound
  • Anti-Inflammatory Agents, Non-Steroidal
  • Azepines
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Core Binding Factor Alpha 2 Subunit
  • Cytokines
  • ETS1 protein, human
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • RUNX1 protein, human
  • Receptors, Cytokine
  • Triazoles

Associated data

  • GEO/GSE71595
  • GEO/GSE71596
  • GEO/GSE71597