Mammalian Period represses and de-represses transcription by displacing CLOCK–BMAL1 from promoters in a Cryptochrome-dependent manner

The mammalian circadian clock is based on a transcription-translation feedback loop (TTFL) consolidated by secondary loops. In the primary TTFL, the circadian locomotor output cycles kaput (CLOCK)–brain and muscle Arnt-like protein-1 (BMAL1) heterodimer acts as the transcriptional activator, and Cry...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 41; pp. E6072 - E6079
Main Authors Chiou, Yi-Ying, Yang, Yanyan, Rashid, Naim, Ye, Rui, Selby, Christopher P., Sancar, Aziz
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 11.10.2016
SeriesPNAS Plus
Subjects
Biological Sciences
Genes
Mammals
PNAS Plus
Proteins
Ribonucleic acid
RNA
Transcription factors
Period
circadian
activator
transcription
DNA binding
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Summary:The mammalian circadian clock is based on a transcription-translation feedback loop (TTFL) consolidated by secondary loops. In the primary TTFL, the circadian locomotor output cycles kaput (CLOCK)–brain and muscle Arnt-like protein-1 (BMAL1) heterodimer acts as the transcriptional activator, and Cryptochrome (CRY) and Period (PER) proteins function as repressors. PER represses by displacing CLOCK–BMAL1 from promoters in a CRY-dependent manner. Interestingly, genes with complex promoters may either be repressed or de-repressed by PER, depending on the particular promoter regulatory elements. Here, using mouse cell lines with defined knockout mutations in clock genes, RNA-seq, ChIP-seq, and reporter gene assays coupled with measurements of DNA–protein interactions in nuclear extracts, we elucidate the dual functions of PER as repressor and de-repressor in a context-dependent manner.
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Contributed by Aziz Sancar, August 17, 2016 (sent for review July 15, 2016; reviewed by Carl Hirschie Johnson and Andrew C. Liu)
1Y.-Y.C., Y.Y., and N.R. contributed equally to this work.
Reviewers: C.H.J., Vanderbilt University; and A.C.L., University of Memphis.
Author contributions: Y.-Y.C., R.Y., and A.S. designed research; Y.-Y.C., Y.Y., and R.Y. performed research; Y.-Y.C., Y.Y., and N.R. analyzed data; and C.P.S. and A.S. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1612917113