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. 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. Circadian rhythms, which are generated by cell autonomous biological clocks, allow for the appropriate temporal synchronization of physiology and behavior, optimizing the efficiency of biological systems (1Panda S. Hogenesch J.B. Kay S.A. Nature. 2002; 417: 329-335Crossref PubMed Scopus (769) Google Scholar, 2Reppert S.M. Weaver D.R. Annu. Rev. Physiol. 2001; 63: 647-676Crossref PubMed Scopus (1212) Google Scholar). In mammals, the circadian timing system is hierarchical, with the master clock located in the hypothalamic suprachiasmatic nuclei (SCN) 1The abbreviations used are: SCN, suprachiasmatic nucleus; CBP, CREB-binding protein; PCAF, p300/CBP-associated factor; RNA Pol II, RNA polymerase II; ChIP, chromatin immunoprecipitation; HAT, histone acetyltransferase; Per, Period; Cry, Cryptochrome; HVSMC, human vascular smooth cells. (3Ralph M.R. Foster R.G. Davis F.C. Menaker M. Science. 1990; 247: 975-978Crossref PubMed Scopus (1415) Google Scholar). Circadian oscillators have been uncovered in both central and peripheral tissues, with the suprachiasmatic nucleus (SCN) coordinating temporal physiology by synchronizing peripheral oscillators through both neural and humoral outputs (4Cheng M.Y. Bullock C.M. Li C. Lee A.G. Bermak J.C. Belluzzi J. Weaver D.R. Leslie F.M. Zhou Q.Y. Nature. 2002; 417: 405-410Crossref PubMed Scopus (593) Google Scholar, 5Kramer A. Yang F.C. Snodgrass P. Li X. 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Positive components include the bHLH-PAS proteins CLOCK and BMAL1 (also known as MOP3) driving transcription as functional heterodimers through E-box enhancer elements (CACGTG) (10Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1555) Google Scholar). NPAS2 (also known as MOP4) is a paralogue of CLOCK and behaves similarly in cell and biochemical assays (8McNamara P. Seo S.B. Rudic R.D. Sehgal A. Chakravarti D. FitzGerald G.A. Cell. 2001; 105: 877-889Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar, 11Hogenesch J.B. Chan W.K. Jackiw V.H. Brown R.C. Gu Y.Z. Pray-Grant M. Perdew G.H. Bradfield C.A. J. Biol. Chem. 1997; 272: 8581-8593Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar, 12Hogenesch J.B. Gu Y.Z. Jain S. Bradfield C.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5474-5479Crossref PubMed Scopus (626) Google Scholar, 13Reick M. Garcia J.A. 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Physiol. 2001; 63: 647-676Crossref PubMed Scopus (1212) Google Scholar). As PER and CRY cytoplasmic levels rise, they can translocate back to the nucleus, and negatively regulate their own transcription by directly interacting with CLOCK:BMAL1 or NPAS2:BMAL1 heterodimers (9Shearman L.P. Sriram S. Weaver D.R. Maywood E.S. Chaves I. Zheng B. Kume K. Lee C.C. van der Horst G.T. Hastings M.H. Reppert S.M. Science. 2000; 288: 1013-1019Crossref PubMed Scopus (1125) Google Scholar, 15Kume K. Zylka M.J. Sriram S. Shearman L.P. Weaver D.R. Jin X. Maywood E.S. Hastings M.H. Reppert S.M. Cell. 1999; 98: 193-205Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar). Thereafter, nuclear levels of the PER/CRY complex decline, relieving repression on the bHLH-PAS heterodimer and restarting the cycle with a period of ∼24 h. The positive limb of the feedback loop also involves the regulation of bmal1, which cycles robustly antiphase to Per and Cry (9Shearman L.P. Sriram S. Weaver D.R. Maywood E.S. Chaves I. Zheng B. Kume K. Lee C.C. van der Horst G.T. Hastings M.H. Reppert S.M. Science. 2000; 288: 1013-1019Crossref PubMed Scopus (1125) Google Scholar). CLOCK and BMAL1 also drive the expression of the orphan nuclear receptor Rev-erbα in the SCN and liver (16Nicolas Preitner F.D. Luis-Lopez-Molina Joszef Zakany Denis Duboule Urs Albrecht Ueli Schibler Cell. 2002; 110: 251-260Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar). The Bmal1 gene contains Rev-Erbα/ROR response elements in its promoter, and its expression is repressed by Rev-Erbα (16Nicolas Preitner F.D. Luis-Lopez-Molina Joszef Zakany Denis Duboule Urs Albrecht Ueli Schibler Cell. 2002; 110: 251-260Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar). Therefore as Per, Cry, and Rev-erbα levels rise, Bmal1 levels fall. The precise regulation of circadian timing systems extends beyond RNA kinetics and includes recently identified transcriptional and post translational modifications (17Eide E.J. Vielhaber E.L. Hinz W.A. Virshup D.M. J. Biol. Chem. 2002; 277: 17248-17254Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 18Lee C. Etchegaray J.P. Cagampang F.R. Loudon A.S. Reppert S.M. Cell. 2001; 107: 855-867Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar). For example, CLOCK, BMAL1, PER1, and PER2 all undergo temporal changes in phosphorylation in mouse liver. These affect their activity, stability, and subcellular localization (18Lee C. Etchegaray J.P. Cagampang F.R. Loudon A.S. Reppert S.M. Cell. 2001; 107: 855-867Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar, 19Kondratov R.V. Chernov M.V. Kondratova A.A. Gorbacheva V.Y. Gudkov A.V. Antoch M.P. Genes Dev. 2003; 17: 1921-1932Crossref PubMed Scopus (206) Google Scholar) Covalent modifications of histones on the chromatin template, such as acetylation, phosphorylation, and methylation, influence gene specific regulation (20Strahl B.D. Allis C.D. Nature. 2000; 403: 41-45Crossref PubMed Scopus (6623) Google Scholar). The correlation between acetylation of core histones and transcriptional induction has been well established (21Grunstein M. Nature. 1997; 389: 349-352Crossref PubMed Scopus (2400) Google Scholar, 22Brownell J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (468) Google Scholar). The association of transcription factors, recruitment of coactivator complexes, and the targeting of gene promoters to induce histone acetylation and chromatin remodeling is a sequential process, resulting in transcriptional activation. Indeed, CREB-binding protein (CBP) is known to associate directly with RNA polymerase II (23Nakajima T. Uchida C. Anderson S.F. Lee C.G. Hurwitz J. Parvin J.D. Montminy M. Cell. 1997; 90: 1107-1112Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar) a critical step in the rapid assembly of functional preinitiation complexes at promoters (24Agalioti T. Lomvardas S. Parekh B. Yie J. Maniatis T. Thanos D. Cell. 2000; 103: 667-678Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar, 25Yie J. Senger K. Thanos D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 13108-13113Crossref PubMed Scopus (98) Google Scholar). For example, p300/CBP-associated factor (PCAF) preferentially acetylate histone H3, while histone H3 and histone H4, are substrates for p300/CBP. Previous reports, linking light exposure during subjective day to histone H3 phosphorylation and associated SCN induction of circadian genes, strongly suggests that chromatin remodeling complexes might temporally regulate rhythmic gene expression exhibited by clock genes in the circadian feedback loop (26Crosio C. Cermakian N. Allis C.D. Sassone-Corsi P. Nat. Neurosci. 2000; 3: 1241-1247Crossref PubMed Scopus (215) Google Scholar). Furthermore, Etchegaray et al. (27Etchegaray J.P. Lee C. Wade P.A. Reppert S.M. Nature. 2003; 421: 177-182Crossref PubMed Scopus (541) Google Scholar) recently demonstrated an important role for histone acetylation in regulating circadian gene expression. These studies examined the role of CLOCK: p300-dependent chromatin remodeling in the liver. We report that this mechanism extends to a distinct peripheral clock in the vasculature where it involves a CLOCK paralogue, NPAS2 and modulates Cry-dependent repression of cyclical gene expression. Cell Culture—HeLa 229 cells were grown to ∼70% confluence and serum shock with 50% fetal bovine serum was carried out as described (8McNamara P. Seo S.B. Rudic R.D. Sehgal A. Chakravarti D. FitzGerald G.A. Cell. 2001; 105: 877-889Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar). Cells were harvested at indicated post-serum induction time points. Animal Handling and Tissue Harvesting—8-12-week-old c57Bl/6 wild-type male mice were synchronized to a 12:12 light/dark cycle for a period of 2 weeks before placing in DD. The animals were anesthetized at indicated time intervals and then exsanguinated. Tissues were harvested, immediately flash-frozen in liquid nitrogen and stored at -70 °C. Chromatin Immunoprecipitation were carried out on cells the assays were on mouse as described S.M. J. Biol. 2001; PubMed Scopus Google Scholar, A.S. S.M. T. Cell. Biol. 2001; PubMed Scopus Google Scholar, J. C.J. S.M. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar) with Cells were in and a for at for cells or at for this in to of were carried out a of and and and II which the of the of human RNA polymerase assays were also in the of or the of to control for was by RNA RNA was cells and mouse and RNA was used in a transcription The resulting for time was to for RNA and were by to and the was used for of all The the intervals serum induction for and RNA expression were the as described was for to for in for RNA expression and a for the control to for in the of promoter, and mPer1 promoter, and and and and and and and and and and In BMAL1, CLOCK, NPAS2, CBP, and were by on and expression by BMAL1, CLOCK, and NPAS2 were with p300 and PCAF, and with or and or with as a control for assays. was the and used in assays as described (8McNamara P. Seo S.B. Rudic R.D. Sehgal A. Chakravarti D. FitzGerald G.A. Cell. 2001; 105: 877-889Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar, S.B. P. S. 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Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) with of protein and with and mouse were and protein A. were carried out as Rhythmic in Chromatin on the gene contains E-box the for heterodimeric bHLH-PAS CLOCK:BMAL1 These of the gene promoter and of which has been to to the regulation of expression A. N. M. M. 2000; PubMed Scopus Google Scholar). In the gene not such of the promoter Cermakian N. Reppert S.M. Sassone-Corsi P. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). in mRNA levels of and in cells serum induction were observed to a circadian expression levels a at and then a cyclical expression at and at by at a at at and assays were on serum cells that the E-box to in the promoter H3 acetylation at while histone acetylation at and which with the of mRNA expression. we not a peak in histone H3 acetylation in the post-serum the peak of histone H3 acetylation at precedes that of mRNA expression of at is in with in vivo in Pol II recruitment was also observed at These are with the temporal recruitment of with to the promoter of genes circadian gene expression. In of and of the bHLH-PAS with coactivator proteins, such as K. S. P. L. EMBO J. 1998; 17: PubMed Google Scholar, A. K. K. J. 1997; PubMed Scopus Google Scholar). of p300/CBP, PCAF, or ACTR with CLOCK, BMAL1, or was observed between all bHLH-PAS proteins and p300 while was observed to associate preferentially with NPAS2 to a with CLOCK with in the of CLOCK and was used as an control and in with the in in assays of complexes between p300/CBP, and and the was specific a complex was not between and of the of the complex S.B. P. S. A. Chakravarti D. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, both p300 and to functional activity, as by histone H3 and histone is to that of p300 or The of p300 or to NPAS2 was also by of CLOCK with in temporal of the proteins in of human vascular smooth cells was of by that CLOCK and p300 both nuclear while NPAS2 is both in the nucleus and in the in cells of with or with of the was for NPAS2 and p300 for CLOCK and p300 In addition, a of NPAS2 and a of used in mammalian assays their association in with the The association of coactivators to clock proteins was then in cells. CLOCK and NPAS2, cell were for the of the coactivator CBP, and p300 with CLOCK to a NPAS2 was CLOCK and not NPAS2 with NPAS2 in these cells the with CLOCK and p300 in the liver (27Etchegaray J.P. Lee C. Wade P.A. Reppert S.M. Nature. 2003; 421: 177-182Crossref PubMed Scopus (541) Google we that the might temporal cells were serum and at intervals were with NPAS2 and the complexes were for a association between NPAS2 and p300 was observed in cells a robust and in synchronized cells The between NPAS2 and p300 at and with was by a at and which with RNA levels of and of was at with a in and mRNA levels was to The that cells a rhythm in histone acetylation the promoter and that NPAS2 in a time-dependent with histone at a time of transcriptional is with regulation of the circadian feedback Transcriptional of by association of the clock bHLH-PAS proteins with the p300/CBP, and is with a role for coactivator recruitment and chromatin remodeling in the temporal regulation of circadian gene activation in the mammalian feedback was by the of overexpression of the on gene transcription in cells. NPAS2:BMAL1 and CLOCK:BMAL1 transcription an mechanism (10Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1555) Google Scholar). and with expression of and and gene activation and In addition, of transcription was and were and of of NPAS2, and the transactivation of BMAL1 by NPAS2, a of the coactivators on the transcription factor complex of these the which is in nuclear receptor and in the of nuclear and is for their Genes Dev. 2000; PubMed Google Scholar). both recruitment of specific coactivators to the clock complex and HAT-dependent activation are critical of E-box activation. Furthermore, the histone acetylation proteins, and D. A. Cell. 1999; 96: Full Text Full Text PDF PubMed Scopus Google Scholar, L. Cell. 1999; 96: Full Text Full Text PDF PubMed Scopus Google Scholar) and the histone complex S.B. P. S. A. Chakravarti D. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google can all E-box activation of NPAS2:BMAL1 for HAT-dependent regulation of these circadian transcriptional of Chromatin and in time was used to mRNA expression of Per (1Panda S. Hogenesch J.B. Kay S.A. Nature. 2002; 417: 329-335Crossref PubMed Scopus (769) Google Scholar, 2Reppert S.M. Weaver D.R. Annu. Rev. Physiol. 2001; 63: 647-676Crossref PubMed Scopus (1212) Google and Rev-erbα was which been in were harvested at a period and Bmal1 in the at and at expression not cycle robustly the period as (9Shearman L.P. Sriram S. Weaver D.R. Maywood E.S. Chaves I. Zheng B. Kume K. Lee C.C. van der Horst G.T. Hastings M.H. Reppert S.M. Science. 2000; 288: 1013-1019Crossref PubMed Scopus (1125) Google Scholar, 18Lee C. Etchegaray J.P. Cagampang F.R. Loudon A.S. Reppert S.M. Cell. 2001; 107: 855-867Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar). In addition, Rev-erbα mRNA was antiphase to that of Bmal1 mRNA is in with the that can Bmal1 expression through to the response elements in the promoter of Bmal1 (16Nicolas Preitner F.D. Luis-Lopez-Molina Joszef Zakany Denis Duboule Urs Albrecht Ueli Schibler Cell. 2002; 110: 251-260Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar). and and in with antiphase to the genes, which drive their and assays were on mouse at and and that the E-box to in the mPer1 promoter with (27Etchegaray J.P. Lee C. Wade P.A. Reppert S.M. Nature. 2003; 421: 177-182Crossref PubMed Scopus (541) Google time-dependent histone H3 acetylation, was observed on the the rhythm is in with the in serum where the peak in histone H3 acetylation at expression at was used to of NPAS2 in mouse temporal changes in both association and of p300 to NPAS2 association was at and with the of mRNA and the in histone H3 acetylation levels on the E-box its promoter and In to regulating CLOCK and BMAL1 have been also to drive Cry expression (10Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1555) Google Scholar, 15Kume K. Zylka M.J. Sriram S. Shearman L.P. Weaver D.R. Jin X. Maywood E.S. Hastings M.H. Reppert S.M. Cell. 1999; 98: 193-205Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar, X. Shearman L.P. Weaver D.R. Zylka M.J. Reppert S.M. Cell. 1999; 96: Full Text Full Text PDF PubMed Scopus Google Scholar). The that association also at peak Cry expression is with a role for HAT-dependent in regulating clock gene expression. E-box transactivation we mediated repression on NPAS2 and gene activation overexpression of was to this that of histone acetylation the target of CRY mediated E-box repression of core histones on target promoters has been to transcriptional gene activation J.E. Allis C.D. Curr. Opin. Genet. Dev. 1996; 6: 176-184Crossref PubMed Scopus (468) Google Scholar). In the the of a rhythm in histone H3 and histone acetylation on the E-box of with transcriptional activation of and is with the heterodimeric complexes of CLOCK, NPAS2 and BMAL1 a histone transcriptional complex to target gene activation. We CBP, PCAF, and ACTR as circadian all of which are known to Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Nature. 1996; PubMed Scopus Google Scholar, Chakravarti D. A. L. Cell. 1997; 90: Full Text Full Text PDF PubMed Scopus Google Scholar). known of the bHLH-PAS such as and the to gene transcription K. S. P. L. EMBO J. 1998; 17: PubMed Google Scholar, A. K. K. J. 1997; PubMed Scopus Google Scholar). We have demonstrated an between both CLOCK and NPAS2 with CBP, PCAF, and ACTR by in assays. this not the of p300 and PCAF, to acetylate core The of CLOCK and NPAS2 with CBP, and were also observed in cells. Indeed, the of to CLOCK and of to NPAS2, the of association of proteins to elements of the clock transcription complex in a which might to activation p300 in a time-dependent with NPAS2 synchronized association was observed at the time of RNA that temporal coactivator recruitment is a step in driving circadian association is at and with Cry2 mediated repression of and with the by Etchegaray et al. (27Etchegaray J.P. Lee C. Wade P.A. Reppert S.M. Nature. 2003; 421: 177-182Crossref PubMed Scopus (541) Google Scholar) that Cry proteins the associated transcriptional coactivator assays an E-box that the transcriptional of CLOCK:BMAL1 and NPAS2:BMAL1 heterodimers is in the of and and a in and are and are known to to transcriptional of both K. K. G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and the of the transcriptional in cells N. T. Lomvardas S. M. G. Thanos D. Science. 2001; PubMed Scopus Google Scholar). In the E-box activation was to by and complexes, which are known to or or the of in regulating circadian gene expression. time-dependent recruitment of chromatin remodeling by NPAS2 was also observed in association of NPAS2 with p300 in acetylation of on histone H3 the E-box on the promoter in mouse which was with circadian in its mRNA The mechanism by which the proteins transcription is K. Zylka M.J. Sriram S. Shearman L.P. Weaver D.R. Jin X. Maywood E.S. Hastings M.H. Reppert S.M. Cell. 1999; 98: 193-205Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar). overexpression of was to this that of histone acetylation the target of E-box repression histone acetylation the on the promoter, chromatin remodeling and assembly of the transcription circadian gene expression in the recruitment of p300 to NPAS2 time-dependent chromatin remodeling and repression is by of complexes on core clock These studies the regulation of circadian rhythms in the system and the role of chromatin remodeling in mammalian circadian We and J. D. for their We all the by and We also C. Bradfield and J. Hogenesch for CLOCK, and and the and S. McKnight for the We also S. Reppert for the of the CLOCK
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