The rhythm of blood

Circadian (from the Latin “about a day”) rhythms are self-sustained, daily oscillations in a wide spectrum of biologic processes including body temperature, blood pressure, sleep and wakefulness, and hormone production. These daily oscillations, or rhythms, are controlled by an endogenous circadian clock. Conceptually, this circadian clock consists of 3 principal components: input pathways, which transmit environmental cues (eg, light); a central pacemaker, which combines these cues with endogenous signals; and output pathways, which convert the signals from the central pacemaker into observable daily oscillations (eg, body temperature). In mammals, the central pacemaker is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus in a group of single-cell circadian oscillators. At least 10 key molecular components of the circadian oscillator have been identified and include the Clock, Tau, Bmal, and Per genes. Traditionally, expression of circadian regulatory genes has been assessed in tissues of the central nervous system.

In this issue of Blood, Boivin and colleagues (page 4143) demonstrate that 4 circadian clock genes (HPER1, HPER2, HPER3, and HDEC1) oscillate in a circadian manner in human peripheral blood mononuclear cells (PBMCs). The experiment was performed in a clinical sleep lab with minimal external stimuli, which allowed the detection of endogenous circadian oscillations. PBMCs were purified and mRNA expression levels were analyzed by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR). All 4 genes studied showed oscillations similar to that of melatonin, a well-characterized circadian marker.

This study demonstrates that circadian clock genes cycle in PBMCs, an easily accessible source of mRNA. It now seems feasible that the impact of various drugs, medical conditions, and physiologic states on the expression of circadian clock genes can readily be studied in the sleep lab. Perhaps most intriguingly, this study provides further impetus for evaluating a possible connection between the circadian clock and the cell-cycle clock. In this context, it is important to note that mice with disruptions of the key circadian clock gene Per2 develop malignant lymphoma and defects in DNA-damage response, suggesting the possibility that it may function as a tumor suppressor gene.