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A molecular mechanism for circadian clock negative feedback.
Hao A Duong1, Maria S Robles, Darko Knutti
1Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|June 18, 2011
Summary
Mammalian circadian rhythms rely on PERIOD (PER) proteins. This study reveals how PER complexes, with PSF and SIN3A, recruit histone deacetylases to repress Per1 transcription, elucidating a key negative feedback mechanism.
Area of Science:
- Chronobiology
- Molecular Biology
- Epigenetics
Background:
- Mammalian circadian rhythms are regulated by a molecular feedback loop involving CLOCK-BMAL1 and PERIOD (PER) proteins.
- The precise molecular mechanism of negative feedback in eukaryotic circadian clocks remains largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanism underlying negative feedback in the mammalian circadian clock.
- To identify the protein constituents of PER complexes and their role in transcriptional repression.
Main Methods:
- Purification and analysis of PER protein complexes from mouse tissues.
- Identification of associated proteins, including PSF (polypyrimidine tract-binding protein-associated splicing factor).
- Investigating the recruitment of SIN3A and histone deacetylases to the Per1 promoter.
Main Results:
- PSF was identified as a component of the PER complex.
- PSF within the PER complex recruits SIN3A, a scaffold for transcriptional inhibitory complexes.
- The PER complex rhythmically delivers histone deacetylases to the Per1 promoter, repressing Per1 transcription.
Conclusions:
- The PER complex, through PSF and SIN3A, provides a molecular mechanism for circadian clock negative feedback.
- This study identifies a novel function for the PER complex in regulating circadian gene expression via epigenetic modification.
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