Epigenetic Control of Cytokine Gene Expression

Abstract

Epigenetics encompasses transient and heritable modifications to DNA and nucleosomes in the native chromatin context. For example, enzymatic addition of chemical moieties to the N-terminal “tails” of histones, particularly acetylation and methylation of lysine residues in the histone tails of H3 and H4, plays a key role in regulation of gene transcription. The modified histones, which are physically associated with gene regulatory regions that typically occur within conserved noncoding sequences, play a functional role in active, poised, or repressed gene transcription. The “histone code” defined by these modifications, along with the chromatin-binding acetylases, deacetylases, methylases, demethylases, and other enzymes that direct modifications resulting in specific patterns of histone modification, shows considerable evolutionary conservation from yeast to humans. Direct modifications at the DNA level, such as cytosine methylation at CpG motifs that represses promoter activity, are another highly conserved epigenetic mechanism of gene regulation. Furthermore, epigenetic modifications at the nucleosome or DNA level can also be coupled with higher-order intra- or interchromosomal interactions that influence the location of regulatory elements and that can place them in an environment of specific nucleoprotein complexes associated with transcription. In the mammalian immune system, epigenetic gene regulation is a crucial mechanism for a range of physiological processes, including the innate host immune response to pathogens and T cell differentiation driven by specific patterns of cytokine gene expression. Here, we will review current findings regarding epigenetic regulation of cytokine genes important in innate and/or adaptive immune responses, with a special focus upon the tumor necrosis factor/lymphotoxin locus and cytokine-driven CD4+ T cell differentiation into the Th1, Th2, and Th17 lineages.

Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

“…KDM6B is one of the two histone demethylases (the other being KDM6A or UTX) that removes the methyl mark from H3K27, relieving the suppression of transcription and inducing an inflammatory response (Falvo, Jasenosky, Kruidenier, & Goldfeld, 2013). Murine studies have confirmed demethylated H3K27 is heavily enriched at IL17a/IL17f locus in Th17 cells and also controls RORγt expression (Mukasa et al, 2010).…”

The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways

“…This process is transcriptionally regulated and involves the induction of lineage-specific transcription factors (Li et al, 2014). Furthermore, complex chromatin remodeling responses that control the accessibility of transcription factors to their target genes provide another regulatory mechanism in Th cell differentiation (Falvo et al, 2013). As compared to other aspects of Th cell induction, signals and pathways that trigger either “permissive” or “repressive” chromatin remodeling responses during Th cell generation remain poorly defined.…”

Cell-composition effects in the analysis of DNA methylation array data: a mathematical perspective

“…However, even the complexity of a given sample may be unknown; even in blood, activation of distinct types of cells may play an important role in some diseases (e.g. [ 25 ]), in which case results of reference-free approaches could in principle depend upon the assumed level of complexity. Thus, critical to the algorithm is its sensitivity of results to choice of a parameter that represents the complexity, the dimension k of the latent linear association driven by cell composition, widely (though perhaps incorrectly) interpreted as the number of cell types.…”