Molecular Regulation of 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 anti-phasic rhythms in activating and repressive modifications generating chromatin states that cycle between transcriptionally permissive and non-permissive. 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).