Abstract
Rhythmic gene expression is central to the circadian control of physiology in mammals. Transcriptional activation of Per and Cry genes by heterodimeric bHLH-PAS proteins is a key event in the feedback loop that drives rhythmicity; however, the mechanism is not clearly understood. Here we show the transcriptional coactivators and histone acetyltransferases, p300/CBP, PCAF, and ACTR associate with the bHLH-PAS proteins, CLOCK and NPAS2, to regulate positively clock gene expression. Furthermore, Cry2 mediated repression of NPAS2:BMAL1 is overcome by overexpression of p300 in transactivation assays. Accordingly, p300 exhibits a circadian time-dependent association with NPAS2 in the vasculature, which precedes peak expression of target genes. In addition, a rhythm in core histone H3 acetylation on the mPer1 promoter in vivo correlates with the cyclical expression of their mRNAs. Temporal coactivator recruitment and HAT-dependent chromatin remodeling on the promoter of clock controlled genes in the vasculature permits the mammalian clock to orchestrate circadian gene expression.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetyltransferases / chemistry*
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Acetyltransferases / metabolism
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Amino Acid Motifs
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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CLOCK Proteins
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Chromatin / chemistry*
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Chromatin / metabolism
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Circadian Rhythm
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Dimerization
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E1A-Associated p300 Protein
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Gene Expression Regulation
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HeLa Cells
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Histone Acetyltransferases
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Histones / chemistry
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Humans
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Mice
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Mice, Inbred C57BL
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Microscopy, Fluorescence
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Myocardium / metabolism
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NIH 3T3 Cells
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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Protein Structure, Tertiary
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RNA / chemistry
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic
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Transcriptional Activation
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Transfection
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Chromatin
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Histones
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NPAS2 protein, human
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Nerve Tissue Proteins
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Npas2 protein, mouse
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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RNA
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Acetyltransferases
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CLOCK Proteins
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CLOCK protein, human
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Clock protein, mouse
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E1A-Associated p300 Protein
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Ep300 protein, mouse
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Histone Acetyltransferases