It is secreted by ∼10% of pacemakers and it modulates clock phase and/or amplitude in pacemaker-specific fashion [12] [14].
This finding suggests that the sympathetic signal is one of important but not the sole factor that modulates clock gene function in cardiovascular tissues [45].
As PER protein cycling appears to be normal in flies with increased LARK expression, the current model for the circadian function of LARK is that it modulates clock outputs, rather than regulating the central molecular oscillator[25], [28].
Additional components feed in light signals to modulate clock behaviour [ 16, 17].
Given the numerous circadianly expressed nuclear receptors, further studies are required to discern which receptors can directly modulate clock activity as opposed to output function.
These analyses revealed different effects of the factors on clock and light-regulated promoter activation, demonstrating various mechanisms by which light-induced transcription factors modulate clock gene expression and thereby transmit photic information to the core clock.
The circadian slave oscillator GRP7 modulates clock output networks [ 4, 10], regulates mRNA export from the nucleus to the cytoplasm during cold stress [ 9], and mediates pathogen defense responses [ 15].
The CRY C-termini are divergent from one another and dispensable for generating the molecular feedback loop, but their deletion alters the period and amplitude of cycling, indicating that they can modulate clock protein function.
We believe it is likely that a small set of transcription factors await to be discovered that can modulate clock function, and just as importantly, we expect that a large set of transcription factors are themselves regulated at the transcript accumulation level to drive the physiological suite of rhythmic outputs.
miR-132 is also induced by photic entrainment cues via a MAPK/CREB-dependent mechanism, modulates clock-gene expression, and attenuates the entraining effects of light [ 64]. miR-31 is a pleiotropic miRNA up-regulated in colorectal tumors and its expression levels are correlated with the stage of the tumor [ 65].
