title: Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor.
abstract: Mammalian circadian rhythms are generated by a negative feedback loop in which PERIOD (PER) proteins accumulate, form a large nuclear complex (PER complex), and bind the transcription factor CLOCK-BMAL1, repressing their own expression. We found that mouse PER complexes include the Mi-2/nucleosome remodelling and deacetylase (NuRD) transcriptional corepressor. Unexpectedly, two NuRD subunits, CHD4 and MTA2, constitutively associate with CLOCK-BMAL1, with CHD4 functioning to promote CLOCK-BMAL1 transcriptional activity. At the onset of negative feedback, the PER complex delivers the remaining complementary NuRD subunits to DNA-bound CLOCK-BMAL1, thereby reconstituting a NuRD corepressor that is important for circadian transcriptional feedback and clock function. The PER complex thus acquires full repressor activity only upon successful targeting of CLOCK-BMAL1. Our results show how specificity is generated in the clock despite its dependence on generic transcriptional regulators and reveal the existence of active communication between the positive and negative limbs of the circadian feedback loop.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Pieter Bas
authors.initials: PB
authors.lastname: Kwak
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: cweitz@hms.harvard.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Weitz
mesh_terms: D000818:Animals; D057906:Circadian Clocks; D025461:Feedback, Physiological; D008099:Liver / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000502:physiology*; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000502:physiology
chemical_list: D021122:Protein Subunits; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex