Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space

Abstract

<jats:title>Abstract</jats:title> <jats:p>All biological processes, living organisms, and ecosystems have evolved with the Sun that confers a 24-hour periodicity to life on Earth. Circadian rhythms arose from evolutionary needs to maximize daily organismal fitness by enabling organisms to mount anticipatory and adaptive responses to recurrent light-dark cycles and associated environmental changes. The clock is a conserved feature in nearly all forms of life, ranging from prokaryotes to virtually every cell of multicellular eukaryotes. The mammalian clock comprises transcription factors interlocked in negative feedback loops, which generate circadian expression of genes that coordinate rhythmic physiology. In this review, we highlight previous and recent studies that have advanced our understanding of the transcriptional architecture of the mammalian clock, with a specific focus on epigenetic mechanisms, transcriptomics, and 3-dimensional chromatin architecture. In addition, we discuss reciprocal ways in which the clock and metabolism regulate each other to generate metabolic rhythms. We also highlight implications of circadian biology in human health, ranging from genetic and environment disruptions of the clock to novel therapeutic opportunities for circadian medicine. Finally, we explore remaining fundamental questions and future challenges to advancing the field forward.</jats:p>

Coupled network of the circadian clocks: a driving force of rhythmic physiology

“…Coupling of myriads of individual tissue clocks across the body into a unified network, re-adjusted on the daily basis by the master pacemaker, ensures temporal coordination of physiology and metabolism [212,[217][218][219][220][221]. Indeed, peripheral clocks operative in the organs play an essential role in temporal coordination of metabolic reactions, from food processing to xenobiotic detoxification, by ensuring anticipation of rest-activity cycles (reviewed in Refs [47,212,218,220,[222][223][224][225][226][227][228]). Large-scale transcriptomic studies indicate that a significant fraction of the transcripts in liver, skeletal muscle, white adipose tissue (WAT), and endocrine pancreas is rhythmic in rodents [34,37,45,227,[229][230][231][232][233][234][235][236][237][238][239][240].…”

“…3; reviewed in Ref. [47,223]). Circadian systems regulate resting energy expenditure and metabolism [412], and even short-term circadian misalignment has been demonstrated to promote reduced glucose tolerance by lowering insulin sensitivity [413].…”

Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

“…Obesity is also tightly linked to disrupted circadian rhythms – 24h cycles that allow organisms to anticipate diurnal changes in physiology and behavior (2–5). Circadian misalignment increases circulating levels of glucose, free fatty acids and triglycerides (6), as well as adversely affecting leptin and ghrelin levels (7), which can have deleterious effects on glucose and energy homeostasis (8).…”

Rheostatic Balance of Circadian Rhythm and Autophagy in Metabolism and Disease

“…Circadian rhythms are daily predictable changes in physiology, behavior and environment with a period of time of approximately 24 h (Greco and Sassone-Corsi, 2020;Kim and Lazar, 2020). They exist on every biological scale, from macroscopic aspects such as sleep-wake cycles to microcosmic phenomena such as the rhythmic abundance of biomolecules (Ryzhikov et al, 2019b;Tan X. et al, 2019;Van Dyck and Casaer, 2019).…”

“…Recent studies have discovered that "clock genes" are essential for circadian rhythm generation (Figure 2; Kim and Lazar, 2020). In the clock gene family, members of the basic helixloop-helix-PAS transcription factor family, BMAL1 and CLOCK, form heterodimers, which bind to E-boxes in the promoters of target genes to activate the expression of the Period (PER1, PER2, and PER3) and Cryptochrome (CRY1 and CRY2) genes (Jahanban-Esfahlan et al, 2018;Gabryelska et al, 2020).…”