rna methylation caused nuclear retention of clock gene transcripts, leading to a longer circadian period. a key feature of clocks is their ability to synchronize to external stimuli. the presence of cell-autonomous oscillators in almost every cell in the body raises the question of how these oscillators are temporally coordinated. the quest for universal timing cues for peripheral clocks in mammals has yielded principal entrainment signals such as feeding, temperature, and oxygen. both feeding rhythms and temperature cycles were shown to synchronize peripheral clocks and even uncouple them from the master clock in the brain (e.g., daytime restricted feeding). recently, oxygen rhythms were found to synchronize clocks in cultured cells. systems biology approaches to elucidate oscillating mechanisms modern experimental approaches using systems biology have identified many novel components in biological clocks that suggest an integrative view on how organisms maintain circadian oscillation. recently, baggs et al. developed a novel strategy termed "gene dosage network analysis" (gdna) to describe network features in the human circadian clock that contribute to an organism's robustness against genetic perturbations. in their study, the authors used small interfering rna (sirna) to induce dose-dependent changes in gene expression of clock components within immortalized human osteosarcoma u2os cells in order to build gene association networks consistent with known biochemical constraints in the mammalian circadian clock. employing multiple doses of sirna powered their quantitative pcr to uncover several network features of the circadian clock, including proportional responses of gene expression, signal propagation through interacting modules, and compensation through gene expression changes. proportional responses in downstream gene expression following sirna-induced perturbation revealed levels of expression that were actively altered with respect to the gene being knocked down. for example, when bmal1 was knocked down in a dose-dependent manner, rev-erba alpha and rev-erba beta mrna levels were shown to decrease in a linear, proportional manner. this supported previous findings that bmal1 directly activates rev-erb genes and further suggests bmal1 as a strong contributor to rev-erb expression. in addition, the gdna method provided a framework to study biological relay mechanisms in circadian networks through which modules communicate changes in gene expression. the authors observed signal propagation through interactions between activators and repressors, and uncovered unidirectional paralog compensation among several clock gene repressors—for example, when per1 is depleted, there is an increase in rev-erbs, which in turn propagates a signal to decrease expression in bmal1, the target of the rev-erb repressors. by examining the knockdown of several transcriptional repressors, gdna also revealed paralog compensation where gene paralogs were upregulated through an active mechanism by which gene function is replaced following knockdown in a non-redundant manner—that is, one component is sufficient to sustain function. these results further suggested that a clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. in essence, the authors proposed that the observed network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation. following this logic, we may use genomics to explore network features in the circadian oscillator. another study conducted by zhang et al. also employed a genome-wide small interfering rna screen in u2os cell line to identify additional clock genes and modifiers using luciferase reporter gene expression. knockdown of nearly 1000 genes reduced rhythm amplitude. the authors found and confirmed hundreds of potent effects on period length or increased amplitude in secondary screens. characterization of a subset of these genes demonstrated a dosage-dependent effect on oscillator function. protein interaction network analysis showed that dozens of gene products were directly or indirectly associate with known clock components. pathway analysis revealed these genes are overrepresented for components of insulin and hedgehog signaling pathway, the cell cycle, and folate metabolism. 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. a systems biology approach may relate circadian rhythms to cellular phenomena that were not originally considered regulators of circadian oscillation. for example, a 2014 workshop at nhlbi assessed newer circadian genomic findings and discussed the interface between the body clock and many different cellular processes. variation in circadian clocks while a precise 24-hour circadian clock is found in many organisms, it is not universal. organisms living in the high arctic or high antarctic do not experience solar time in all seasons, though most are believed to maintain a circadian rhythm close to 24 hours, such as bears during torpor. much of the earth's biomass resides in the dark biosphere, and while these organisms may exhibit rhythmic physiology, for these organisms the dominant rhythm is unlikely to be circadian. for east-west migratory organisms—and especially those organisms that circumnavigate the globe—the absolute 24-hour phase might deviate over months, seasons, or years. some spiders exhibit unusually long or short circadian clocks. some trashline orbweavers, for example, have 18.5-hour circadian clocks, but are still able to entrain to a 24-hour cycle. this adaptation may help the spiders avoid predators by allowing them to be most active before sunrise. black widows' clocks are arrhythmic, perhaps due to their preference for dark environments.