Central and peripheral signals set the circadian liver clock

Anyone who has experienced jet lag will understand the importance of a smooth-running circadian clock. Crossing time zones decouples our biological rhythms from the natural cycle of light and dark were used to. We perceive light cues through retinal photoreceptors that relay signals to the suprachiasmatic nucleus (SCN) in the brain. "Phase adjustments" in peripheral tissues ensure that each clock follows the same schedule. These can be set indirectly through SCN-dependent biological rhythms, such as feeding cycles or body temperature. How synchronizing cues operate at the molecular level, however, remains obscure. One key question is whether cyclically expressed genes in peripheral tissues are controlled by local circadian clocks or by systemic cues that are directly or indirectly controlled by the SCN pacemaker.

In a new study published online this week in the open access journal PLoS Biology, Benot Kornmann, Ueli Schibler, and colleagues investigated circadian genes in the liver to try and answer this question. To determine whether genes were under local or systemic control, they generated a mouse strain with conditionally active liver clocks that they could turn on or off at will.

The authors modified a transcription factor called REV-ERBa that shuts down circadian gene expression via suppression of a clock gene Bmal1. The modified gene had tetracycline-responsive elements (TREs), that respond to tetracycline and similar antibiotics. Mice with this modification were bred with a strain carrying a gene construct that activates the elements specifically in liver cells. In transgenic offspring fed with tetracycline-like doxycyline (Dox), Rev-erba remained silent in liver cells and Bmal1 functioned normally. In the absence of Dox, transgenic offspring overexpressed REV-ERBa, and Bmal1 was inactive, effectively turning off the liver clocks.

When the authors performed a genome-wide scan of the expression of genes targeted by BMAL1 in t

Contact: Natalie Bouaravong
Public Library of Science

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