Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation

Abstract

Acute systemic inflammation from infectious and noninfectious etiologies has stereotypic features that progress through an initiation (proinflammatory) phase, an adaptive (anti-inflammatory) phase, and a resolution (restoration of homeostasis) phase. These phase-shifts are accompanied by profound and predictable changes in gene expression and metabolism. Here, we review the emerging concept that the temporal phases of acute systemic inflammation are controlled by an integrated bioenergy and epigenetic bridge that guides the timing of transcriptional and post-transcriptional processes of specific gene sets. This unifying connection depends, at least in part, on redox sensor NAD(+)-dependent deacetylase, Sirt1, and a NF-κB-dependent p65 and RelB feed-forward and gene-specific pathway that generates silent facultative heterochromatin and active euchromatin. An additional level of regulation for gene-specific reprogramming is generated by differential expression of miRNA that directly and indirectly disrupts translation of inflammatory genes. These molecular reprogramming circuits generate a dynamic chromatin landscape that temporally defines the course of acute inflammation.

Figure 1.. Phase-shifts during inflammation.

(A) The initiation, adaptation, and resolution phases associated with acute systemic inflammation. The magnitude of the initiation phase determines the duration of the adaptation phase and whether the process eventually resolves by returning to homeostasis. The adaptation phase involves repression of sets of proinflammatory genes that initiate the inflammation and activation of anti-inflammatory, antimicrobial, and metabolism genes. The resolution phase of acute inflammation implies restoration of homeostasis. (B) The sustained proinflammatory phase associated with chronic inflammatory diseases such as obesity, diabetes, and atherosclerosis, where there is no apparent switch to an adaptive phase, and resolution is uncommon.

Figure 2.. Epigenetics regulate phase-shifts during acute systemic inflammation.

TLR sensors and NF-κB p65-dependent signaling pathways activate transcription of rapid response proinflammatory genes, such as TNF-α, to initiate inflammation. This requires de-repression of poised basal promoters followed by transcription initiation and elongation. A p65-dependent, feed-forward loop induces RelB expression, which transfers to the nucleus and accumulates at promoters of proinflammatory and anti-inflammatory genes. RelB is required to direct assembly of a multicomponent repressor complex, which silences specific genes at specific loci by generating facultative (reversible) heterochromatin. As a dual transcription regulator, it also activates transcription of euchromatin by binding to specific gene loci. Together, these events contribute to the plasticity of chromatin during acute systemic inflammation, and reversal of this code portends resolution and survival.

Figure 3.. TLR sensing and signaling integrate with metabolism, bioenergetics, and epigenetics to guide phase-shifts during acute systemic inflammation.

In this model, NAD⁺ sensor Sirt1 and NF-κB factors form the bridge between metabolism and epigenetic reprogramming. Recognition: TLRs are poised to sense danger from microbes or alarming host molecules and immediately convey information to cells by signaling pathways that include NF-κB. Initiation: TLR pathways rapidly modify basal metabolism (elevate glycolysis and oxidative phosphorylation), increase ATP/AMP, and decrease NAD⁺NADH ratios to de-repress promoters and activate transcription of acute proinflammatory genes by acetylating and phosphorylating histones (H3 and H1) and transcription factors (NF-κB p65). Adaptation: TLR-NF-κB p65-dependent, feed-forward processes reprogram metabolism (decrease oxidative phosphorylation and glucose flux) and shift bioenergy (reduce ATP, increase Nampt-dependent NAD⁺ production) to promote Sirt1-dependent, gene-specific chromatin modifications by deactivating p65 and inducing RelB and its promoter loading. Resolution: Epigenetic-driven mitochondrial biogenesis restores bioenergetics, rebalances metabolism, and deprograms chromatin to re-arm the cell and re-establish homeostasis.

Figure 4.. Differential regulation of translation during acute systemic inflammation.

TLR sensors generate differential expression of miR-125b, -221, and -579, which together with protein mediators TIAR, TTP, and AUF, form a RISC, which enhances degradation of TNF-α mRNA and disrupts the translation apparatus. This post-transcriptional effect, which develops during the adaptive phase, plays a role in shifting the initiation phase to the adaptive phase and exists independent of transcription repression. Like transcription silencing, it is reversible. Ago2, Argonaute 2; ARE, Au-rich element; CDE, constitutive decay element.