Genome-wide has been performed. Epigenomically similar regions

Genome-wide epigenetic analysis for histone modifications and chromatin accessibility in rheumatic diseases is still at an early stage, although epigenetic changes at disease-relevant genes have been detected in rheumatic disease samples47.

Gene enhancers are altered in monocytes in systemic lupus erythematosus (SLE)48. Gene regulatory elements exhibit changes in histone 3 lysine 4 trimethylation (H3K4me3) in SLE, especially at elements important in IFN signaling49. ATAT-seq showed changes in chromatin accessibility in B cells near genes involved in cell activation50. In RA fibroblast-like synoviocytes (FLS)51, epigenetic profiling of various histone modifications such as H3K27ac, H3K4me1, H3K4me3 and H3K36me3 and open chromatin has been performed. Epigenomically similar regions exist in RA FLS cells relative to OA controls and are associated with active enhancers and promoters of immune-related genes.

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Although these studies represent an important step forward for epigenomic analysis in complex rheumatic diseases, it is still a major challenge to translate epigenetic regulation into patterns of gene expression that define cell activation state and phenotype. Another important concept that will be useful in future research is that chromatin-mediated epigenetic mechanisms participate in memory-like phenomena that can either enhance or inhibit inflammatory responses52, which may provide new insights to interpret the dysregulation of immune response in rheumatic diseases. Epigenetically mediated immunological imprinting can manifest as tolerance53 or training54, which suppress inflammation or enhance it, respectively. Tolerant macrophages exhibit a selective downregulation of chromatin accessibility and active histone marks such as H3K4me3 and H3K27ac at promoters and enhancers of inflammatory genes55,56, as well as a defect in TLR signaling53.

In trained monocytes, distal regulatory elements gain H3K27ac and persistent H3K4me1 marks. Upon re-stimulation, genomic regions containing H3K4me1 marks are quickly recognized and acetylated to promote rapid and enhanced transcriptional responses54. Both tolerance and training represent clinically relevant functional states and the development of innate memory has been shown to be relevant to inflammation52,53. Tolerance is part of the immune paralysis that occurs during bacterial sepsis or late phases of septic shock.

Interestingly, microbiome-derived LPS subtypes can affect endotoxin tolerance and the emergence of autoimmune diseases such as diabetes57. Also, type I interferon, which is an abundant cytokine in many rheumatic diseases, can abolish macrophage tolerance in a chromatin-dependent manner55,58. Conversely to tolerance mechanisms, epigenetic-mediated training of monocytes can contribute to nonspecific protective effects of vaccination that strongly influence susceptibility to secondary infections52. Furthermore, ?-glucan-induced trained immunity can counteract tolerance-related epigenetic changes56.

A recent study showed that training or tolerization of innate immunity in the peripheral leads to stable epigenetic reprogramming of microglia in the brain, which in turn affects pathogenesis in Alzheimer’s and stroke disease models59. This study supports the concept that environmental stimuli acting at distal sites can affect inflammatory responses in distinct tissues such as RA synovium, thereby contributing to pathogenesis. Overall, tolerance and training are likely initial examples of a more pervasive phenomenon of epigenetic-mediated conditioning by exposure to environmental challenges including chronic inflammation. Induction of innate immune memory may be important for diseases characterized by dysregulation of immune responses and it will be interesting to determine whether defects in establishing tolerance and training states contribute to rheumatic diseases. Numerous studies have shown that the vast majority of disease-associated allelic variants fall outside protein-coding sequences and instead lie in cis-regulatory regions such as gene enhancers60-64; this includes common autoimmune-disease associated polymophisms65. Lupus associated polymorphisms in the HLA and BANK1 loci have been studied in depth through large-scale efforts, and have been implicated as eQTLs that control gene expression66,67. As few disease-associated eQTLs have been mapped relative to large numbers of disease-associated SNVs, it is a major challenge to assign distal enhancers that harbor disease-associated allelic variants to their target genes, and to determine causal relationships between these variants, gene expression and disease states. Advances that begin to address causal links between chromatin landscape and function (gene expression) include techniques to study chromatin conformation and looping42, and CRISPR-Cas9-mediated genome editing68.

Techniques that map chromatin contacts such as Hi-C42 have recently been combined with ChIP (termed Hi-ChIP) to map protein-centric chromatin interactions in as few as 50,000 cells69. HiChIP with the positive histone mark H3K27ac was used to generate high-resolution maps of enhancer–promoter contacts in primary human T cells, and to map the target genes of enhancers that harbor autoimmune disease-associated allelic variants. This approach will provide a valuable framework for mapping distal cis-regulatory regions and disease-associated variants to target genes in rheumatic diseases. CRISPR-Cas9-mediated genome editing enables targeted manipulation of the epigenome to determine how epigenetic mechanisms affect cell function and activation68. This approach has been used to support the disease-relevant importance of an enhancer in the TNFAIP3 locus70.

Utilization of a nuclease-deficient Cas9 fused with functional domains of epigenetic regulators such as KRAB, TET1 or p300 allows targeting of these proteins to specific regulatory regions to determine the role of epigenetic marks in gene expression and cell function71. Overall, the CRISPR-Cas9 system can be used to determine which genes are regulated by disease-associated enhancers, and which epigenetic mechanisms regulate gene expression in rheumatic diseases. Such epigenetic mechanisms can potentially be therapeutically targeted to ameliorate autoimmunity and inflammation.


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