Chronomics of pressure overload-induced cardiac hypertrophy in mice reveals altered day/night gene expression and biomarkers of heart disease.

There is critical demand in contemporary medicine for gene expression markers in all areas of human disease, for early detection of disease, classification, prognosis, and response to therapy. The integrity of circadian gene expression underlies cardiovascular health and disease; however time-of-day profiling in heart disease has never been examined. We hypothesized that a time-of-day chronomic approach using samples collected across 24-h cycles and analyzed by microarrays and bioinformatics advances contemporary approaches, because it includes sleep-time and/or wake-time molecular responses.

Clock gene expression during chronic inflammation induced by infection with Trypanosoma brucei brucei in rats.

African sleeping sickness is characterized by alterations in rhythmic functions. It is not known if the disease affects the expression of clock genes, which are the molecular basis for rhythm generation. We used a chronic rat model of experimental sleeping sickness, caused by the extracellular parasite Trypanosoma brucei brucei (Tb brucei), to study the effects on clock gene expression.

Global transcriptome analysis reveals circadian regulation of key pathways in plant growth and development.

Background: As nonmotile organisms, plants must rapidly adapt to ever-changing environmental conditions, including those caused by daily light/dark cycles. One important mechanism for anticipating and preparing for such predictable changes is the circadian clock. Nearly all organisms have circadian oscillators that, when they are in phase with the Earth's rotation, provide a competitive advantage.

Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day.

Molecular gene cycling is useful for determining body time of day (BTOD) with important applications in personalized medicine, including cardiovascular disease and cancer, our leading causes of death. However, it impractically requires repetitive invasive tissue sampling that is obviously not applicable for humans. Here we characterize diurnal protein cycling in blood using high-throughput proteomics; blood proteins are easily accessible, minimally invasive, and can importantly serve as surrogates for what is happening elsewhere in the body in health and disease.

Disturbed diurnal rhythm alters gene expression and exacerbates cardiovascular disease with rescue by resynchronization.

Day/night rhythms are recognized as important to normal cardiovascular physiology and timing of adverse cardiovascular events; however, their significance in disease has not been determined. We demonstrate that day/night rhythms play a critical role in compensatory remodeling of cardiovascular tissue, and disruption exacerbates disease pathophysiology. We use a murine model of pressure overload cardiac hypertrophy (transverse aortic constriction) in a rhythm-disruptive 20-hour versus 24-hour environment.

Nuclear receptor expression links the circadian clock to metabolism.

As sensors for fat-soluble hormones and dietary lipids, oscillations in nuclear receptor (NR) expression in key metabolic tissues may contribute to circadian entrainment of nutrient and energy metabolism. Surveying the diurnal expression profiles of all 49 mouse nuclear receptors in white and brown adipose tissue, liver, and skeletal muscle revealed that of the 45 NRs expressed, 25 are in a rhythmic cycle and 3 exhibit a single transient pulse of expression 4 hr into the light cycle. While thyroid hormones are generally constant, we find that TRalpha and beta dramatically cycle, suggesting that fundamental concepts such as "basal metabolism" may require reexamination.

Transient T cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720.

FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is an orally available immunomodulatory agent that induces severe peripheral blood lymphopenia. Most studies of these lymphopenic effects have been limited to short-term exposure to FTY720. FTY720 alters the ability of lymphocytes to respond to sphingosine-1-phosphate (S1P) through S1P receptors, particularly S1P1.

Day/night rhythms in gene expression of the normal murine heart.

Molecular circadian oscillators have recently been identified in heart and many other peripheral organs; however, little is known about the physiologic significance of circadian gene cycling in the periphery. While general temporal profiles of gene expression in the heart have been described under constant lighting conditions, patterns under normal day/night conditions may be distinctly different. To understand how gene expression contributes to cardiac function, especially in human beings, it is crucial to examine these patterns in 24-h light and dark environments.

Effects of aging on central and peripheral mammalian clocks.

Circadian organization changes with age, but we do not know the extent to which age-related changes are the result of alterations in the central pacemakers, the peripheral oscillators, or the coupling mechanisms that hold the system together. By using transgenic rats with a luciferase (luc) reporter, we assessed the effects of aging on the rhythm of expression of the Period 1 (Per1) gene in the suprachiasmatic nucleus (SCN) and in peripheral tissues. Young (2 months) and aged (24-26 months) Per1-luc transgenic rats, entrained to light-dark cycles, were killed, and tissues were removed and cultured.

Coordinated transcription of key pathways in the mouse by the circadian clock.

In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver.

Circadian rhythms in isolated brain regions.

The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus has been referred to as the master circadian pacemaker that drives daily rhythms in behavior and physiology. There is, however, evidence for extra-SCN circadian oscillators. Neural tissues cultured from rats carrying the Per-luciferase transgene were used to monitor the intrinsic Per1 expression patterns in different brain areas and their response to changes in the light cycle.