Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

Abstract

Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional-translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear "hubs" of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control.

Keywords: chromatin; circadian rhythms; epigenetics; nuclear organization.

Fig. 1.

Transcriptional–translational loops control circadian rhythms in mammals. The positive loop is driven by the transcription factors CLOCK:BMAL1, which activate the expression of clock-controlled genes through binding to E-box elements at their promoters. Per and Cry genes give rise to the components of the negative loop. Thus, PER and CRY proteins heterodimerize in the cytoplasm and are stabilized by phosphorylation events catalyzed by associated kinases (CKε/δ). The PER/CRY complex translocates into the nucleus and inhibits CLOCK:BMAL1 activity. F BOX proteins act in concert with the proteasome to degrade the PER/CRY complex with 24-h rhythmicity, yielding to a new round of transcription by CLOCK:BMAL1. Several transcription factors (TFs), including DBP/TEF/E4BP4 and RORs/REV-ERBs, are then acting to initiate additional oscillations in downstream genes, through rhythmic binding to D-box and ROR elements, respectively. These interconnected loops generate the circadian output, which is apparent in rhythms in metabolism, energy levels, hormone secretion, and many other biological pathways, depending on the tissue and environmental conditions.

Fig. 2.

The nuclear landscape and circadian interactome. (A) Circos plot representing the genome-wide view of dbp circadian interactions (black lines) with the corresponding chromosomes in trans, named Dbp circadian interactome. The gene content for each Dbp contact region is indicated in the outer layer of the plot. In red color are the names of circadian genes in MEFs. Each chromosome is represented as a color code, which is indicated on the right. The inner layers represent frequencies of interaction for WT or Bmal1^−/− MEFs. Reprinted with permission from ref. . (B) Chromosome positioning in the nucleus is not random, and each chromosome occupies its own territory. Chromosomes intermingle in hubs and delineate the framework for chromatin functions. Circadian genes are positioned in transcriptionally active and gene-rich environments, delineating circadian interactomes. E-box elements cluster together in the nucleus, generating nuclear compartments supporting circadian transcription. Chromatin dynamics coordinate circadian cycles in clustering of certain circadian genes, possibly colocalizing at shared transcription factories in the nucleus. These nuclear regions might be highly enriched in regulatory proteins, including RNA polymerase II (Pol II), chromatin remodelers, and transcription factors (TFs). Thereby, CLOCK:BMAL1 specialized transcription factories might exist.

Fig. 3.

NAD⁺ and sirtuins interconnect cellular compartments and control metabolism during the circadian cycle. NAD⁺ levels are circadian, as the rate-limiting enzyme NAMPT is encoded by a clock-controlled gene (94, 95). Rhythms on the availability of NAD⁺ impose rhythmicity to the NAD⁺-dependent deacetylases known as sirtuins. SIRT1 and SIRT6 regulate circadian rhythms in the nucleus, and SIRT3 in the mitochondria (32, 111). In the cell nucleus, SIRT1 and SIRT6 exert different control mechanisms on CLOCK:BMAL1 and specific transcription factors such as SREBP1, resulting in a SIRT6- and SIRT1-specific partitioning of the circadian genome in genomic subdomains, paralleled by differential metabolic phenotypes (32). Similarly, rhythms in SIRT3 activity elicit cycles of deacetylation at mitochondrial proteins, including enzymes involved in fatty-acid oxidation. Acetylation of these proteins controls their functionality, and, thereby, rhythms in fatty-acid oxidation are observed.