The term circadian derives from the Latin circa (about) dies (a day), since when taken away from external cues (such as environmental light), they do not run to exactly 24 hours.
[1] The normal body clock oscillates with an endogenous period of exactly 24 hours, it entrains, when it receives sufficient daily corrective signals from the environment, primarily daylight and darkness.
Circadian oscillators are ubiquitous in tissues of the body where they are synchronized by both endogenous and external signals to regulate transcriptional activity throughout the day in a tissue-specific manner.
[3] The basic molecular mechanisms of the biological clock have been defined in vertebrate species, Drosophila melanogaster, plants, fungi, bacteria,[4][5] and presumably also in Archaea.
[10][11] The SCN itself is located in the hypothalamus, a small region of the brain situated directly above the optic chiasm, where it receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract.
[13] Through the analysis of per circadian mutants and additional mutations on Drosophila clock genes, a model encompassing positive and negative autoregulatory feedback loops of transcription and translation has been proposed.
[14][15] Studies in cyanobacteria, however, changed our view of the clock mechanism, since it was found by Kondo and colleagues that these single-cell organisms could maintain accurate 24-hour timing in the absence of transcription, i.e. there was no requirement for a transcription-translation autoregulatory feedback loop for rhythms.
[20] More importantly, redox oscillations as demonstrated by peroxiredoxin rhythms have now been seen in multiple distant kingdoms of life (eukaryotes, bacteria and archaea), covering the evolutionary tree.
[22][23] Therefore, the model of the clock has to be considered as a product of an interaction between both transcriptional circuits and non-transcriptional elements such as redox oscillations and protein phosphorylation cycles.
[26][27][28][29] Several mammalian clock genes have been identified and characterized through experiments on animals harboring naturally occurring, chemically induced, and targeted knockout mutations, and various comparative genomic approaches.
[26] The majority of identified clock components are transcriptional activators or repressors that modulate protein stability and nuclear translocation and create two interlocking feedback loops.
Negative feedback is achieved by PER:CRY heterodimers that translocate back to the nucleus to repress their own transcription by inhibiting the activity of the CLOCK:BMAL1 complexes.
[5] Another regulatory loop is induced when CLOCK:BMAL1 heterodimers activate the transcription of Rev-ErbA and Rora, two retinoic acid-related orphan nuclear receptors.
In bacterial circadian rhythms, the oscillations of the phosphorylation of cyanobacterial Kai C protein was reconstituted in a cell free system (an in vitro clock) by incubating KaiC with KaiA, KaiB, and ATP.
and co-workers identified methylation of internal adenosines (m6A) within mRNA (notably of clock transcripts themselves) as a key regulator of the circadian period.
These observations clearly demonstrated the importance of RNA-level post-transcriptional regulation of the circadian clock, and concurrently established the physiological role of (m6A) RNA methylation.
In response to light stimulus, the body corresponds with a system and network of pathways that work together to determine the biological day and night.
Fustin and co-workers provided a new layer of complexity to the regulation of circadian oscillator in mammals by showing that RNA methylation was necessary for efficient export of mature mRNA out of the nucleus: inhibition of RNA methylation caused nuclear retention of clock gene transcripts, leading to a longer circadian period.
The quest for universal timing cues for peripheral clocks in mammals has yielded principal entrainment signals such as feeding, temperature, and oxygen.
In addition, the GDNA method provided a framework to study biological relay mechanisms in circadian networks through which modules communicate changes in gene expression.
These results further suggested that a clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function.
Protein interaction network analysis showed that dozens of gene products were directly or indirectly associate with known clock components.
Coupled with data demonstrating that many of these pathways are clock-regulated, Zhang et al. postulated that the clock is interconnected with many aspects of cellular function.
For example, a 2014 workshop[37] at NHLBI assessed newer circadian genomic findings and discussed the interface between the body clock and many different cellular processes.