Interferon target-gene expression and epigenomic signatures in health and disease

Abstract

Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak-STAT signaling pathway and induce overlapping patterns of expression, called 'interferon signatures', of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an 'interferon epigenomic signature' by activating latent enhancers and 'bookmarking' chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.

Fig. 1 |. IFN-induced signaling and overlapping patterns of gene expression.

Type I and II IFNs activate distinct canonical signaling pathways leading to activation of ISGF3 and STAT1 homodimers, respectively, and downstream induction of ISRE- and GAS-driven target genes. The patterns of genes induced by type I and II IFNs overlap, partly because target genes can contain both ISRE and GAS elements, and overlap may be secondary to induction of transcription factors with shared target genes. This cascade of transcription factors, particularly IRF family members, which can interact with STATs and redirect their binding activity, can mediate the evolution of IFN signatures over time. Type I and II IFNs also activate noncanonical transcriptional complexes and additional STATs, and induce the expression of unphosphorylated STATs, thus contributing to the IFN signature.

Fig. 2 |. Nucleic acid sensors and downstream signaling pathways induce type I IFN production.

Cytosolic sensors of RNA (RIG-I and MDA5) and of DNA (cGAS) signal via the adaptors MAVS and STING, respectively, and activate the kinases TBK1 and IKKε and downstream IRF3 (left). IRF3 translocates to the nucleus, where it cooperates with NF-κB in driving Ifnb transcription in multiple cell types including macrophages, epithelial cells and fibroblasts. In pDCs that produce large amounts of IFN-α, nucleic-acid-containing immune complexes are endocytosed via Fc receptors (FcR) and delivered to endosomes, and then activate TLR sensors of RNA (TLR7, TLR8) or DNA (TLR9) (right). These endosomal TLRs signal via the adaptor MyD88 and activate IKK-kinase complexes, which in turn activate downstream transcription factors including IRF7 and the NF-κB subunits p50 and p65. IRF5 is activated by a yet-unknown mechanism. These transcription factors translocate to the nucleus and drive Ifna transcription. pDCs express cell-surface receptors including BDCA2, CD123 and ILT7, which inhibit IFN-α production through mechanisms that have not been fully clarified. EBV, Epstein–Barr virus; EBERs, EBV-encoded small RNAs; dsRNA, double-stranded RNA; ssRNA, single-stranded RNA; L1, LINE 1; TRAF, TNF receptor associated factor; RBP, RNA-binding protein.

Fig. 3 |. epigenomic regulation links type I IFN signaling to induction of inflammatory non-ISgs.

Stimulation of macrophages with TNF leads to transient expression of TNF-target genes encoding inflammatory mediators, such as IL6 and TNF, followed by a state of tolerance in which signaling responses to TLR ligands are strongly suppressed, and chromatin is not activated (not depicted). In contrast to tolerization with TNF alone, co-stimulation with TNF plus IFN-α results in coordinate binding of IRFs and NF-κB, increased chromatin accessibility and increased positive histone marks, most notably H3K4me3 (top right). These genes are thereby bookmarked with primed chromatin and subsequently exhibit a robust transcriptional response even to very weak proximal TLR-induced signals, such as those in TNF-tolerized cells on TLR stimulation (bottom right). TSS, transcription start site; ac, acetyl; Pol, polymerase.