Circadian Regulation of Immunity Through Epigenetic Mechanisms

Abstract

The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. A specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. Hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. Interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. This clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. Immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. Hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. Certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.

Keywords: chromatin; circadian rhythm; epigenetics; infection; transcriptional regulation.

Figure 1

Transcriptional-translational feedback loops control circadian gene expression. Rhythmic binding to e-boxes on chromatin of the clock components of the positive loop, CLOCK:BMAL1, induce the expression of clock-controlled genes and the clock negative regulators PER and CRY. Additionally, the nuclear receptor REV-ERBα and ROR impose transcriptional rhythms on genes via RORE cis regulatory elements, while the PAR-bZIP transcription factors DBP, and the repressor NFIL3 interplay to drive transcriptional rhythms in a set of genes through binding to D-boxes. Blue arrows relate molecular components of the clock TTFL involved in epigenetic regulation of the indicated mechanisms of immunity and infection, which are further discussed across the text.

Figure 2

Epigenetic regulatory mechanisms at the core of circadian function in the immune system. Circadian trafficking in the bloodstream is observed for many types of immune cells. In Ly6Chi inflammatory monocytes, circadian trafficking is regulated by an epigenetic mechanism involving molecular interactions between the circadian TF BMAL1 and the Polycomb repressive complex to regulate levels of the H3K27 methylation at the promoters of chemokine genes. In macrophages, transcription of regulatory genes appears cyclic, and the clock component REV-ERBα could be responsible by inhibiting enhancer function together with the TF PU.1, and their location is coincident with the enhancer mark H3K4me1 (black dots). Intestinal epithelial cells are components of the mucosal barrier in the gut, hence they participate in host-pathogens interactions. In these cells, the repressor complex REB-ERBα-NCoR-HDAC3 rhythmically deacetylate histones to promote chromatin compaction and cyclic silencing of genes involved in host pathogens interactions, and this mechanism could also participate in regulating circadian responses to infection. Differentiation of dendritic cells is orchestrated by the TF STAT3. The circadian HDAC SIRT1 deacetylates and inactivates STAT3, and this mechanism could be implicated in circadian regulation of differentiation and proliferation of T cells.