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termination complex to the Per and Cry genes. 7 In addition, the transcription
of Bmal1 is alternatively regulated by its own transcription targets, the
nuclear receptors Rev-erba / b (the repressors) and Rora (the activator). 8-10
The multiple interlocked autoregulatory feedback loops result in a robust
circadian variation in the expression and activity of Bmal1 over a 24-h
period, providing a driving force for circadian oscillation of the molecular
clockwork.
The circadian regulators also target clock-controlled genes to generate
circadian rhythms in all major cellular processes in both SCN neurons and
peripheral organs, resulting in a rhythmic expression of 3-10% of all mRNAs
expressed in a given tissue due to time-dependent interactions between the
circadian regulators with specific gene promoter sequences, transcription
factors, or transcriptional initiation, elongation, and termination complexes,
as well as the key factors controlling chromatin remodeling. 7,11-15 The
clock-controlled genes usually do not share overlapping expression patterns
between tissues, suggesting a key role for the circadian clock in controlling
tissue-specific function in vivo . Clock-controlled genes expressed in all the
tissues studied include the key regulators of cell proliferation, metabolism,
senescence, and DNA damage response. 16-23
The molecular clock in SCN neurons and peripheral tissues can be
entrained or phase-shifted by cellular signaling. The most potent circadian
time cue for the SCN clock is light, which is received by a subset of
melanopsin-expressing retinal ganglion cells and transmitted directly to
the SCN neurons via the retinohypothalamic tract (RHT). Upon activation,
the RHT produces neurotransmitters that activate a cascade of signal trans-
duction events leading to circadian phase resetting. 24,25 Although the SCN
clock is capable of generating autonomic circadian outputs on its own, the
constant coupling of the central clock with environmental cues provides a
survival advantage by synchronizing daily physiology and behavior with
local time cues. 25,26 A shift in environmental cues, such as traveling across
several time zones on an aircraft, induces a phase-shift in the central clock
and the subsequent SCN-controlled phase shift in peripheral tissues via cir-
cadian output pathways to reestablish the endogenous circadian homeostasis
to the new local time. The number of days needed to fully adjust to the new
time zone is dependent on the number of time zones crossed during the
trip. Constant back-and-forth phase shifts of environmental light cues
resulting from rotating work schedules or chronic jet lag disrupt endogenous
circadian homeostasis by uncoupling the central and peripheral clock
coordination. 27-29
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