Histone acetyltransferase-dependent chromatin remodeling and the vascular clock.
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.
Curtis
Anne M
AM
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Seo
Sang-beom
SB
Westgate
Elizabeth J
EJ
Rudic
Radu Daniel
RD
Smyth
Emer M
EM
Chakravarti
Debabrata
D
FitzGerald
Garret A
GA
McNamara
Peter
P
D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002940:Circadian Rhythm; D019281:Dimerization; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D000123:Acetyltransferases; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002843:Chromatin; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012313:RNA; D015534:Trans-Activators; D014157:Transcription Factors; C104264:NPAS2 protein, human; C491259:Npas2 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse; C494361:Ep300 protein, mouse