MAMMALIAN CIRCADIAN BIOLOGY: Elucidating Genome-Wide Levels of Temporal Organization

Abstract

During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle.

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…BMAL1, the key transcription factor heterodimerizing with CLOCK or NPAS2, drives circadian expression of other clock genes and the clockcontrolled genes. 38,[85][86][87] REV-ERBa is another core clock gene whose expression is regulated by the BMAL1/CLOCK heterodimer, and REV-ERBa in turn represses BMAL1 expression. 49 DEC2 and DBP are both involved in the core clock network, 51,54 but they have been also considered clock-controlled genes responsible for downstream gene regulation.…”

Clock gene expression in peripheral leucocytes of patients with type 2 diabetes

“…The circadian system is responsible for regulating a variety of physiological and behavioural processes, including feeding behaviour and energy metabolism [1,2]. Recent studies revealed that the circadian clock system consists essentially of a set of clock genes [1,2].…”

“…Recent studies revealed that the circadian clock system consists essentially of a set of clock genes [1,2]. The circadian clock resides in the hypothalamic suprachiasmatic nucleus (SCN), which is recognised as being the master clock, and the same clock exists also in almost all peripheral tissues, including liver, heart, kidney [3][4][5] and leucocytes [6][7][8].…”

“…The resultant PER and CRY proteins heterodimerise, translocate to the nucleus, and inhibit the activity of CLOCK-BMAL1, thus forming a transcriptional-translational feedback loop. In parallel, the CLOCK-BMAL1 heterodimer activates the transcription of various clock-controlled genes [1,2]. Given that some clock-controlled genes also serve as transcription factors, the expression of numerous genes may be tied to the functions of the circadian clock [1,2].…”

The clock gene Per2 links the circadian system to the estrogen receptor

“…The central clock, through neural, hormonal and metabolic signals, synchronizes the peripheral oscillators, which in turn drive the expression of downstream clock-controlled genes in a tissue-specific manner (Panda et al, 2002;Storch et al, 2002;Miller et al, 2007). Consequently in various tissues, circadian rhythms impinge upon many physiological processes and pathological conditions, including cancer (Fu et al, 2002;Matsuo et al, 2003;Lowrey and Takahashi, 2004;Ko and Takahashi, 2006). Recent studies suggested that circadian disruption is associated with breast tumorigenesis (Hansen, 2001;Chen et al, 2005).…”