Mammalian circadian clock and metabolism – the epigenetic link

Abstract

Circadian rhythms regulate a wide variety of physiological and metabolic processes. The clock machinery comprises complex transcriptional–translational feedback loops that, through the action of specific transcription factors, modulate the expression of as many as 10% of cellular transcripts. This marked change in gene expression necessarily implicates a global regulation of chromatin remodeling. Indeed, various descriptive studies have indicated that histone modifications occur at promoters of clock-controlled genes (CCGs) in a circadian manner. The finding that CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyl transferase (HAT) activity has paved the way to unraveling the molecular mechanisms that govern circadian chromatin remodeling. A search for the histone deacetylase (HDAC) that counterbalances CLOCK activity revealed that SIRT1, a nicotinamide adenin dinucleotide (NAD+)-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of aging, inflammation and metabolism. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link between energy balance, chromatin remodeling and circadian physiology. Here we review recent studies that support the existence of this link and discuss their implications for understanding mammalian physiology and pathology.

Coordination of the transcriptome and metabolome by the circadian clock

“…Circadian physiology reveals that strong connections between the circadian clock and cellular metabolism exist (1,(51)(52)(53)(54)(55)(56), but the extent to which these occur and the nature of these interactions have been largely unappreciated. This study reveals a comprehensive and integrative map of the diurnal metabolome in the liver and provides a detailed depiction of the dynamic interfaces between the metabolome, proteome, and transcriptome.…”

Diurnal expression ofDnmt3bmRNA in mouse liver is regulated by feeding and hepatic clockwork

“…Glucose homeostasis and lipid homeostasis in the liver exhibit a circadian pattern, which is known to at least in part be dependent on the diurnal variation in expression of metabolism-related genes. 54,55 The circadian rhythm of metabolism-related genes has been reported to be regulated by epigenetic histone modifications. 43 Since there is still no clear evidence linking the diurnal change in DNA methylation to the circadian gene expression and subsequent hepatic functions associated with metabolism, future studies measuring precise promoter methylation states in individual glucose and lipid homeostasis-related genes along with the time of day may lead to a better understanding of the link between the diurnal Dnmt3b variation and liver physiology.…”

Attenuated Expression and Gelsolin in Association with Induction of Aquaporin-1 and Nitric Oxide Synthase in Dysfunctional Hearts of Aging Mice Exposed to Endotoxin

“…In vivo footprinting studies of the gelsolin promoter region have shown that the transcription factors Sp I and activating transcription factor (ATF)-l and epigenetic regulation of the promoter region through histone deacetylation [trichostatin A (TSA) and apicidin] represent main transcriptional mechanisms regulating the expression of gelsolin. Similar to the nuclear factor NFKB, the regulatory activity of gelsolin-specific transcription factors and the gelsolin-specific histone deacetylase (HDAC) can be modulated by aging (27) and agerelated diseases, such as cancer (28).…”