Epigenetic mechanisms in inflammation

Abstract

Epigenetic modifications occur in response to environmental changes and play a fundamental role in gene expression following environmental stimuli. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Diet, pollution, infections, and other environmental factors have profound effects on epigenetic modifications and trigger susceptibility to diseases. Despite a growing body of literature addressing the role of the environment on gene expression, very little is known about the epigenetic pathways involved in the modulation of inflammatory and anti-inflammatory genes. This review summarizes the current knowledge about epigenetic control mechanisms during the inflammatory response.

Figure 1.

Environment and the epigenome. Differential expression of genes is dependent on chromatin organization. This organization is composed of DNA, nucleosomes, non-histone proteins, transcription factors, chromatin-modifying enzymes, and regulatory RNAs collectively known as the epigenome. The epigenome is sensitive to stress, toxins, nutrition, infections, and other environmental factors with long-term consequences for gene regulation and age-related diseases.

Figure 2.

Epigenetic mechanisms of gene repression. (A) The open chromatin structure of an active gene with an unmethylated promoter region. The nucleosomes have activation marks such as acetylation (red circles) and H3K4 methylation (blue circles). The RNA Polymerase complex (Pol-II) and transcription factors (TFs) bind to the promoter and initiate transcription. (B) Gene repression by the Polycomb repressive complexes (PRC1 and PRC2) is mediated by the DNA-binding protein JARID2 and accompanied by H3K27 methylation (green circles), loss of H3K4 methylation, and deacetylation of nucleosomes. (C) DNA methylation (light blue circles) is mediated by the HP1-dependent recruitment of DNA methyltransferases (DNMTs) and the H3K9 methyltransferase G9a. Methyl-binding proteins (MeCP2 or members of the MBP family) bind to the methylated DNA and recruit histone deacetylase complexes (HDACs). Brown circles indicate H3K9 methylation. Overall, gene silencing is accompanied by the chromatin compaction, loss of histone activation marks, and removal of transcription factors. (D) An epigenetic mechanism dependent on microRNA, MeCP2, and Polycomb. In hepatic stellate cells, translation of the MeCP2 transcript is blocked by miR-132. Upon myofibroblast transdifferentiation, down-regulation of miR-132 enables activation of MeCP2, which binds to the PPARγ promoter and recruits H3K9 histone methyltransferases and the HP1 repressor. In addition, MeCP2 stimulates chromatin condensation by recruiting PRC1 and PRC2. This eventually leads to repression of the PPARγ transcription.

Figure 3.

The regulatory circuit during oncogenic transformation. NF-κB, IL6, let-7 microRNA, and Lin28B are key components of the positive feedback loop underlying the epigenetic switch from normal to transformed cells. The switch is induced by an initial inflammatory signal (Src activation) that activates NF-κB, which turns on IL6 transcription and inhibits let-7 microRNA via Lin28B. The resulting high levels of IL6 activate NF-κB, thereby completing the positive feedback loop that maintains the transformed phenotype.