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.