Missing link found between circadian clock and metabolism

Sirtuins came to mind, he said, because of their dependence on NAD+, a factor that is often considered a readout of metabolic state. SIRT1 also preferentially deacetylates the same histone that they showed CLOCK acetylates. Like CLOCK, Sirtuins are known to modify proteins other than histones as well, he added.

Now, Sassone-Corsi's team shows that the HDAC activity of the SIRT1 enzyme is controlled in a circadian manner, correlating with rhythmic acetylation of histones and the clock component BMAL1 by CLOCK. SIRT1 also associates with CLOCK and is recruited to the CLOCK:BMAL1 chromatin complex at circadian promoters, where they turn on the transcription of other clock genes, they report. Treatments that block SIRT1 activity lead to disturbances in the circadian cycle and in the acetylation of histones and BMAL1. Finally, in mice lacking SIRT1 only in the liver, they found evidence that SIRT1 normally contributes to circadian control in a living animal.

Asher and Schibler's team made a similar discovery: They show that SIRT1 is required for high-magnitude circadian activity of several core clock genes. SIRT1 binds CLOCK-BMAL1 in a circadian manner, they report, and promotes the deacetylation and degradation of the clock component called PER2. " It's been dogma for years that the circadian clock is regulated by transcription feedback loops," Sassone-Corsi said. "Now we have another loop—an enzymatic loop."

The next step is to understand the connection between changes in metabolism and the circadian cycle in more detail, the researchers said.

The findings also open a door on the possibility that epigenetics might influence behavior, Sassone-Corsi added, with potential implications for understanding the obesity epidemic.

" Genetics can't be the answer because the incidence is on the rise," he said. "Something else must be going on and perhaps epigenetic regulation is the key. In broad terms, that's where we're going."

Article 1:

The researchers include Yasukazu Nakahata, University of California, Irvine, CA; Milota Kaluzova, University of California, Irvine, CA; Benedetto Grimaldi, University of California, Irvine, CA Saurabh Sahar, University of California, Irvine, CA; Jun Hirayama, University of California, Irvine, CA; Danica Chen, Massachusetts Institute of Technology, Cambridge, MA; Leonard P. Guarente, Massachusetts Institute of Technology, Cambridge, MA; and Paolo Sassone-Corsi, University of California, Irvine, CA.

Article 2:

The researchers include Gad Asher, University of Geneva, Geneva, Switzerland; David Gatfield, University of Geneva, Geneva, Switzerland; Markus Stratmann, University of Geneva, Geneva, Switzerland; Hans Reinke, University of Geneva, Geneva, Switzerland; Charna Dibner, University of Geneva, Geneva, Switzerland; Florian Kreppel, University of Ulm, Ulm, Germany; Raul Mostoslavsky, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Frederick W. Alt, Howard Hughes Medical Institute, Children's Hospital, Center for Blood Research, and Department of Genetics, Harvard University Medical School, Boston, MA; and Ueli Schibler, University of Geneva, Geneva, Switzerland.