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.

ChIP-seq in Studying Epigenetic Mechanisms of Disease and Promoting Precision Medicine: Progresses and Future Directions

“…ChIP-seq also revealed the alterations of H3K27ac in autoimmune disease [46], such as Crohn's disease [47] and juvenile idiopathic arthritis [10] and in neurodegenerative disease like Parkinson's disease [48]. In these cases, disease-associated SNPs often reside in enhancers or super-enhancers.…”

“…There are several hundred chromatin regulators in the human genome that encode enzymes that 'write,' 'read' or 'remove' histone modifications [28]. Chromatin regulators are emerging therapeutic targets of the epigenetic drugs in cancer [45,52] and noncancer disease therapy [10]. Histone deacetylase and Janus kinase 2 (a histone phosphorylation writer) inhibitors have been approved for cancer therapy [63], and more epigenetic drugs are currently in clinical or preclinical trials [21,45].…”

“…Therefore, it is often difficult to directly compare different datasets due to the variability in antibody sensitivity, specificity and reproducibility, epitope 10.2217/epi-2016-0053 www.futuremedicine.com future science group ChIP-seq in studying epigenetic mechanisms of disease & promoting precision medicine: progresses & future directions Perspective abundance, as well as experimental inconsistency [64,71]. To allow comparison across different samples, mapped reads are typically normalized to the same library size, like reads or fragments per million.…”

Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

“…For example, the BET inhibitors JQ1, I-BET762 and I-BET151 were shown to reduce the production of proinflammatory cytokines in monocytes and macrophages stimulated by LPS in vitro and in mice 120. Studies on human inflamed joint synovial fluid show that treatment with JQ1 on CD4+ memory/effector T cells preferentially inhibited the expression of genes involved in proinflammatory and cytokine-related processes regulated by super-enhancers 121. Although BET inhibitors have not been studied in the context of IBD, their immune-modulating potential points to promising effects for IBD treatment.…”

Biogenesis and Transcriptional Regulation of Long Noncoding RNAs in the Human Immune System

“…In mammalian cells, thousands of enhancers are active and up to 1 million enhancers have been postulated to be active in all human cells (93). Super enhancers are clusters of typical enhancers marked by a very high density of the p300 histone acetyltransferase and H3K27Ac (94–96). Transcription factor density at these regions is also particularly high and seminal work by Richard Young and colleagues has found that these regions are particularly sensitive to perturbation of Mediator and members of the bromodoman and extraterminal (BET) subfamily of bromodomain proteins (94, 96).…”