Plasticity and specificity of the circadian epigenome

Abstract

Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of an appreciable portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate on how epigenetic processes are involved in creating transcriptional environments that are permissive to tissue-specific gene expression programs, which work in concert with the circadian machinery. Accumulating data show that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events. A detailed understanding of the communication cues between the central and peripheral clocks is crucial for a more complete understanding of the circadian system and the several levels of control that are implicated in maintaining biological timekeeping.

Fig. 1. The circadian CLOCK network

The core circadian transcription factors, CLOCK and BMAL1, direct E-box mediated transcription of clock controlled genes (CCGs), including activators and repressors of the circadian system. PER and CRY protein translation occurs at night and subsequently causes repression of the core CLOCK:BMAL1 transcriptional complex. Degradation of the PER/CRY repressors prompts a new circadian cycle whereby CLOCK:BMAL1 transcription is reinitiated. In addition to transcriptional regulation, post-translational modifications play a critical role in the modulation of circadian proteins. Here only phosphorylation is schematically presented. This can be elicited by a number of kinases including CKIε, CKIδ, CK2α, GSK3β and AMPK. Other post-translational modifications of clock proteins include acetylation, sumoylation and ubiquitination. RRE, REV-ERB/ROR response element; CK, Casein kinase; GSK3β, glycogen synthase kinase-3 beta; P, phosphorylation.

Fig. 2. What underlies the different genomic responses of central versus peripheral clocks?

Approximately 10% of transcripts in a given tissue display circadian expression. Of all oscillatory transcripts in each tissue (here schematically represented as a circle for SCN, liver and muscle), only a fraction of ~5-10% is common between two given tissues, and that fraction decreases drastically when intersecting more than two tissues (the yellow area in the middle of the circles)^{, -}. These differences can be accounted by the contribution of tissue-specific transcription factors (TFs) which interplay with the circadian machinery (here simplistically represented by the CLOCK:BMAL1 complex). The differential composition of these complexes in different tissues and circadian times might bestow selectivity of recruitment to chromatin loci corresponding to promoters of CCGs.

Fig. 3. Chromatin remodeling and the circadian clock

Directed chromatin-modifying events responsible for rhythmic CCG transcription, comprise a major portion of the circadian epigenome. Our current understanding of post-translational modifications of the H3 tail suggests that phosphorylation (serine 10), acetylation (lysine 9/14) and methylation (lysine 4/27) are associated to circadian transcription. Some chromatin modifiers may be directly or indirectly modulated by the circadian system. Acetylation of non-histone proteins can also occur in a clock-dependent manner, this is the case for BMAL1 and the GR. The involvement of the NAD⁺-dependent deacetylase SIRT1 in circadian control and its physical interaction with CLOCK revealed a link between circadian clock and cellular metabolism^, . The metabolic state of the cell has a robust response on epigenetic control, and some metabolic cues have been found to oscillate. The extent to which the circadian clock regulates the metabolic state of the cell is only beginning to emerge, and the full elucidation of these concepts is awaited.