Review
Molecular Regulation of Circadian Chromatin

https://doi.org/10.1016/j.jmb.2020.01.009Get rights and content

Highlights

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    Chromatin modifications and chromatin remodeling are integral to circadian clock transcription.

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    Circadian chromatin involves cycles of activating and repression modifications.

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    Circadian regulated facultative heterochromatin involves deacetylation, histone H3 lysine 9 methylation, and HP1binding.

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    Changes to genome structure occur over the circadian cycle.

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    Age-related changes to circadian output likely occur because of changes to circadian chromatin.

Abstract

Circadian rhythms are generated by transcriptional negative feedback loops and require histone modifications and chromatin remodeling to ensure appropriate timing and amplitude of clock gene expression. Circadian modifications to histones are important for transcriptional initiation and feedback inhibition serving as signaling platform for chromatin-remodeling enzymes. Current models indicate circadian-regulated facultative heterochromatin (CRFH) is a conserved mechanism at clock genes in Neurospora, Drosophila, and mice. CRFH consists of antiphasic rhythms in activating and repressive modifications generating chromatin states that cycle between transcriptionally permissive and nonpermissive. There are rhythms in histone H3 lysine 9 and 27 acetylation (H3K9ac and H3K27ac) and histone H3 lysine 4 methylation (H3K4me) during activation; while deacetylation, histone H3 lysine 9 methylation (H3K9me) and heterochromatin protein 1 (HP1) are hallmarks of repression. ATP-dependent chromatin-remodeling enzymes control accessibility, nucleosome positioning/occupancy, and nuclear organization. In Neurospora, the rhythm in facultative heterochromatin is mediated by the frequency (frq) natural antisense transcript (NAT) qrf. While in mammals, histone deacetylases (HDACs), histone H3 lysine 9 methyltransferase (KMT1/SUV39), and components of nucleosome remodeling and deacetylase (NuRD) are part of the nuclear PERIOD complex (PER complex). Genomics efforts have found relationships among rhythmic chromatin modifications at clock-controlled genes (ccg) revealing circadian control of genome-wide chromatin states. There are also circadian clock-regulated lncRNAs with an emerging function that includes assisting in chromatin dynamics. In this review, we explore the connections between circadian clock, chromatin remodeling, lncRNAs, and CRFH and how these impact rhythmicity, amplitude, period, and phase of circadian clock genes.

Graphical abstract

A subset of mechanisms involved in circadian clock regulation with a focus on chromatin-associate events. The schematic depicts generalized factors required for proper circadian clock function that are the subject of this review. (RNA, The red solid line; DNA, black solid line; nucleosomes, gray cylinders).

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Section snippets

The Circadian Clock

The circadian clock is an anticipatory system synchronized to daily changes in light and temperature. The circadian clock regulates behavioral and metabolic rhythms along with a host of molecular processes ensuring gene expression is appropriately timed based on cellular needs [[1], [2], [3], [4], [5]]. At its core, the circadian rhythm is generated by a cell-autonomous molecular oscillator arranged as a transcriptional negative feedback loop [[6], [7], [8]]. The core clock proteins lack strong

Circadian Chromatin

Chromatin is the DNA protein complex that packages DNA in the nucleus and is predominantly arranged into repeated array of canonical nucleosomes composed of histone octamers containing 2 H2A, 2 H2B, 2 H3, and 2 H4, further condensed and organized into 30 nm fibers and beyond [61,62]. Post-translational modifications to chromatin serve as signaling scaffold ensuring genome elements are either accessible or compacted depending on cellular needs. Compaction and accessibility are controlled by

Histone Acetylation and Deacetylation

Circadian oscillations in chromatin modifications also include acetylation and deacetylation. Thus it is not surprising that histone lysine acetyltransferases (KATs) and HDACs generate a rhythm in histone acetylation [96,119]. Since the discovery, Gcn5 is a KAT, the role of histone acetylation as a mark for actively transcribed genes is well-established [[120], [121], [122]] while deacetylation is a requisite for heterochromatin [123]. Much of our understanding of acetylation and deacetylation

ATP-dependent Chromatin-remodeling Enzymes

Circadian post-transcriptional modifications to chromatin are interpreted by effectors including ATP-dependent remodeling enzymes; although, what modifications recruit which remodeling enzymes is sorely lacking. The list of ATP-dependent remodeling enzymes is relatively large and include Clockswitch (CSW-1), Chromodomain helicase DNA binding 1 (CHD1), Clock ATPase (CATP), SWI/SNF (SWItch/sucrose nonfermentable), and Ino80 in Neurospora, KISMET and BRAHMA in Drosophila, and CHD3/CHD4 and SWI/SNF

Chromatin Structure

In addition to chromatin remodeling at the nucleosome level, the circadian clock controls 24-h cycles of gene transcription in part by regulating the 3-D chromatin architecture. Current models on nuclear structure indicate chromosomes are organized into nonrandom polymers that undergo dynamic changes to support metabolism, transcription profiles and development [145,146]. Thus, it is perhaps not surprising there are changes to genome structure on the circadian timescale beyond the localized

Long Noncoding RNAs and Chromatin Organization

There is a substantial body of research showing long noncoding RNAs (lncRNAs) regulate chromatin and growing evidence indicates this holds true, in some instances, for circadian lncRNAs. lncRNAs and small RNAs arise from intergenic or antisense transcription and are key regulators of chromatin structure at noncircadian regulated loci [152,153]. High-throughput, strand-specific RNA sequencing has revealed that antisense transcripts are widespread throughout the genome in many species [154] and

Circadian Clock, Aging, and Disease

Circadian rhythms have profound influence on human health and disruption of the circadian clock contributes to cancer, cardiovascular disease, neuroendocrine disorders, metabolic syndromes, and others (Fig. 6) [[177], [178], [179]]. A major driver of circadian-related disease undoubtedly resides in global misregulation of ccg expression because the clock controls more than 40% of protein coding transcripts either directly or indirectly [172,180]. Altering expression of just a few critical genes

Concluding Remarks

It is now unequivocal that a major function of the clock is to control chromatin states and genome structure to facilitate proper amplitude and timing of circadian regulated gene expression. A conserved model of circadian heterochromatin involving deacetylation, H3K9me2/3, HP1 binding, and dynamic DNA methylation is part and parcel of negative feedback inhibition. In addition, the circadian clock is involved in regulating the dynamics of nuclear architecture. The connection between circadian

Acknowledgments

The authors apologize to colleagues whose work they were unable to cite. Especially all the great works carried out in Arabidopsis. Work presented in this report was supported by grants from the National Institute of Food and Agriculture (NE1939) to WJB and China Scholarship Council (CSC #201406270116) to QZ.

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