Abstract
Gene expression is known to be a stochastic phenomenon. The stochastic gene expression rate is thought to be altered by topological change of chromosome and/or by chromatin modifications such as acetylation and methylation. Changes in mechanical properties of chromosome/chromatin by soluble factors, mechanical stresses from the environment, or metabolites determine cell fate, regulate cellular functions, or maintain cellular homeostasis. Circadian clock, which drives the expression of thousands of genes with 24-hour rhythmicity, has been known to be indispensable for maintaining cellular functions/homeostasis. During the last decade, it has been demonstrated that chromatin also undergoes modifications with 24-hour rhythmicity and facilitates the fine-tuning of circadian gene expression patterns. In this review, we cover data which suggests that chromatin structure changes in a circadian manner and that NAD+ is the key metabolite for circadian chromatin remodeling. Furthermore, we discuss the relationship among circadian clock, NAD+ metabolism, and aging/age-related diseases. In addition, the interventions of NAD+ metabolism for the prevention and treatment of aging and age-related diseases are also discussed.
Highlights
In humans, each cell has a nucleus, the diameter of which is ∼10 μm, packing approximately 2 m long DNA if stretched end to end
It has been indicated that MLL1 is an acetylated protein and its deacetylation, following the inactivation is controlled by SIRT1 [40], suggesting that regulation of SIRT1/6 activity is the key for circadian changes of chromatin property by H3K9/14ac and H3K4me3
highfat diet (HFD), which remodeled circadian clock and completely ablated oscillations in cellular NAD+ in mouse liver, drove an altered circadian gene expression pattern [18]. These reports indicate that proper circadian NAD+ regulation is indispensable for the maintenance of circadian clock, suggesting that it is probably essential for preservation of health
Summary
Each cell has a nucleus, the diameter of which is ∼10 μm, packing approximately 2 m long DNA if stretched end to end. Chromosomes in the nucleus are known to be present nonrandomly, located at the spatially confined regions; for example, euchromatin prefers center and heterochromatin periphery of nucleus [2, 3] Despite their relatively low abundance in the cell, transcription factors have to search for their target gene, usually existing in only 2 copies per cell, to activate or repress in such a spatially messy condition [4]. Histone modifications, such as acetylation, phosphorylation, methylation, and ubiquitination, bring about transient, nonheritable modifications in the genome, which increase or decrease the stochastic gene expression rates [10, 11] These modifications alter stochastic gene expression rates by changing the property of chromatin surface. The interventions of NAD+ metabolism for the prevention and treatment of aging and age-related diseases are discussed
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