The circadian epigenome: how metabolism talks to chromatin remodeling

Abstract

Circadian rhythms occur in most of the living organisms, and with a 24 hour periodicity govern a number of physiological and metabolic functions. During the past few years, an important research effort has uncovered new trails that intersect between circadian rhythms and metabolic pathways. At a molecular level, the clock machinery is responsible for the establishment of a circadian epigenome, and this can be modulated by metabolic cues. Indeed, metabolic control by the circadian clock is manifest in the development of metabolic diseases when circadian rhythms are impaired. Thus, pharmacological modulation of circadian rhythms promises new avenues for the treatment of metabolic and sleep disorders.

Figure 1. Chromatin remodeling in the circadian clock

The epigenetic mechanisms that underlie clock controlled gene transcription are on the way to be uncovered. Chromatin modifying enzymes act in synchrony for the fine tuning necessary to achieve clock-controlled gene expression. Transcriptional activators coordinate rhythmic hyperacetylation and H3K4 trimethylation at circadian gene promoters that promote transcription. Conversely, repressors remove acetylation marks and promote a closed state of the chromatin fiber at the clock controlled gene promoters that inhibit transcription. Thus, activator and repressor enzymes act in a very precise synchrony that coordinates the circadian transcription of about 10% – 15% of all transcripts.

Figure 2. Clock-regulated metabolite availability can be “sensed” by chromatin remodeling enzymes and effect circadian gene expression

Clock-controlled program of gene expression dictates the circadian oscillation of a portion of the transcriptome. A number of these genes encode enzymes and proteins that exert control on metabolic pathways and metabolite availability. Some of these metabolites, such as NAD⁺, ATP, Acetyl-CoA or maybe glucose, could be used as cofactors by chromatin remodeling enzymes that modify histone tails leading to phosphorylation (P), acetylation (Ac) or methylation (Me). These epigenetic modifications are associated with changes in gene transcription and other chromatin functions. Thus, metabolite availability could affect the activity of chromatin modifiers and may constitute a regulatory mechanism for gene expression [35].

Figure 3. Clock-controlled NAD⁺ levels regulate enzymatic activity of SIRT1 and PARP1

Intracellular levels of NAD⁺ oscillate in a circadian manner, and this oscillation is driven by the molecular clock. CLOCK:BMAL1 complexes rhythmically bind to E-boxes at the Nampt gene promoter, directing its circadian transcription. The resulting NAMPT protein is a key rate-limiting enzyme in the NAD⁺ salvage pathway, which dictates the circadian biosynthesis of NAD⁺. This metabolite feeds back into the clock by serving as a cofactor for SIRT1 and PARP1 enzymes, whose enzymatic activity is circadian. SIRT1 and PARP1 directly target CLOCK:BMAL1 complexes to change their transactivational activity. A molecular interplay between SIRT1 and PARP1 exists, and depends on NAD+ levels. By this mechanism, NAD⁺ intersects in between a transcriptional and an enzymatic feedback loop to regulate energy homeostasis.