Gene-specific epigenetic regulation in serious infections with systemic inflammation

Abstract

Inflammation is a fundamental biologic process that is evolutionally conserved by a germ line code. The interplay between epigenetics and environment directs the code into temporally distinct inflammatory responses, which can be acute or chronic. Here, we discuss the epigenetic processes of innate immune cells during serious infections with systemic inflammation in four stages: homeostasis, incitement, evolution, and resolution. We describe feed-forward loops of serious infections with systemic inflammation that create gene-specific silent facultative heterochromatin and active euchromatin according to gene function, and speculate on the role of epigenetics in survival.

Fig. 1

Gene reprogramming during serious infection with SSI. Gene expression during SSI is depicted as occurring in four temporally distinct phases: poised; incitement; evolution; resolution. Following derepression of poised promoters, induction of rapidresponse proinflammatory genes incites an acute proinflammatory phase, which is rapidly terminated by posttranslational processes. The evolving phase is characterized by activated or repressed gene expression, according to function: rapid response proinflammatory genes that incited SSI are transcriptionally repressed by formation of facultative heterochromatin, and antiinflammatory and antimicrobial genes are activated from a euchromatin state. A return to homeostasis with reversal of facultative heterochromatin occurs during the resolving phase.

Fig. 2

Distinct combinations of protein, histone and DNA modifiers acting on proximal promoters direct the phenotypic phases of SSI (component details are provided in the text). Poised: a complex of p50 homodimers, transcription corepressors and epige netic histone-silencing modifications combine in a checkpoint to prevent constitutive transcription. Inciting: TLRdependent processes derepress the promoters of rapid-response genes, leading to p65/p50 transactive heterodimer formation and competent transcription. Not shown is the rapid disassembly of the p65/p50 heterodimer by p65 proteosome degradation (see fig. 1 and text). Evolving: A p65-dependent feed-forward loop induces RelB de novo, after which it both initiates gene-selective facultative heterochromatin formation to silence acute proinflammatory gene promoters and activates antiinflammatory gene promoters. Resolution is not shown but includes diminishing RelB production and reversal of chromatin modifications.

Fig. 3

Nucleosomes reposition at the TNF α promoter during SSI. The proximal promoter, about −500 bp, is depicted, showing the K2 and K3 (active) κ B regulatory cis elements. During the poised state, nucleosome 1 covers K3. The LPS TLR4 inciting phase directs p65 binding and repositions nucleosomes 1 and 2 by a Nap1 histone 2A.Z chaperone. The RelB-initiated evolving phase repositions nucleosome 2 over the K3 kB site, where it remains after TL4 stimulation (endotoxin tolerance). The interdependent, multicomponent silencing complex that condenses chromatin by histone and DNA methylation is sustained as facultative heterochromatin during SSI evolution. RelB removal by siRNA repositions nucleosome 2 by ATPdependent BAF complex. It is not known how naturally resolving SSI repositions nucleosomes to generate a competent promoter.