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Factor 1 As a Circadian Transcription Factor Differential Display of DNA Downloaded from genesdev.cshlp.org on August 4, 2008 - Published by Cold Spring Harbor Laboratory Press Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor Hans Reinke, Camille Saini, Fabienne Fleury-Olela, Charna Dibner, Ivor J. Benjamin and Ueli Schibler Genes & Dev. 2008 22: 331-345 Access the most recent version at doi:10.1101/gad.453808 Supplementary "Supplemental Research Data" data http://genesdev.cshlp.org/cgi/content/full/22/3/331/DC1 References This article cites 69 articles, 24 of which can be accessed free at: http://genesdev.cshlp.org/cgi/content/full/22/3/331#References Article cited in: http://genesdev.cshlp.org/cgi/content/full/22/3/331#otherarticles Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the service top right corner of the article or click here Notes To subscribe to Genes and Development go to: http://genesdev.cshlp.org/subscriptions/ © 2008 Cold Spring Harbor Laboratory Press Downloaded from genesdev.cshlp.org on August 4, 2008 - Published by Cold Spring Harbor Laboratory Press Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor Hans Reinke,1 Camille Saini,1 Fabienne Fleury-Olela,1 Charna Dibner,1 Ivor J. Benjamin,2 and Ueli Schibler1,3 1Department of Molecular Biology, University of Geneva, CH-1211 Geneva, Switzerland; 2Health Science Center, University of Utah, Salt Lake City, Utah 84132, USA The circadian clock enables the anticipation of daily recurring environmental changes by presetting an organism’s physiology and behavior. Driven and synchronized by a central pacemaker in the brain, circadian output genes fine-tune a wide variety of physiological parameters in peripheral organs. However, only a subset of circadianly transcribed genes seems to be directly regulated by core clock proteins. Assuming that yet unidentified transcription factors may exist in the circadian transcriptional network, we set out to develop a novel technique, differential display of DNA-binding proteins (DDDP), which we used to screen mouse liver nuclear extracts. In addition to several established circadian transcription factors, we found DNA binding of heat-shock factor 1 (HSF1) to be highly rhythmic. HSF1 drives the expression of heat-shock proteins at the onset of the dark phase, when the animals start to be behaviorally active. Furthermore, Hsf1-deficient mice have a longer free-running period than wild-type littermates, suggesting a combined role for HSF1 in the mammalian timekeeping and cytoprotection systems. Our results also suggest that the new screening method DDDP is not limited to the identification of circadian transcription factors but can be applied to discover novel transcriptional regulators in various biological systems. [Keywords: Circadian rhythms; HSF1; in vitro screen] Supplemental material is available at http://www.genesdev.org. Received August 17, 2007; revised version accepted November 28, 2007. Circadian oscillation of biological processes has been de- loops in clock gene expression (Hardin et al. 1990). In scribed in organisms ranging from photosynthetic bacte- mammals, the CLOCK and BMAL1 transcription factors ria to vertebrates and reflects the existence of underlying activate the expression of Per and Cry genes. Once the intrinsic biological clocks with near 24-h oscillation pe- PER and CRY proteins reach a critical concentration riods (Hardin 2006). Circadian control of physiology and and/or activity, they attenuate the CLOCK/BMAL1-me- behavior in mammals is driven by a master pacemaker diated activation of their own genes in a negative feed- located in the suprachiasmatic nuclei (SCN) of the hy- back loop (Reppert and Weaver 2002). In addition, several pothalamus. Rhythmicity in the SCN is entrained by post-translational events, such as the control of protein external Zeitgeber cues, such as daily changes in light phosphorylation, degradation, and nuclear entry, con- intensity, and further transmitted to peripheral organs tribute critically to the generation of daily oscillations in (Saper et al. 2005). Studies using transgenic rodents and clock gene products (Lee et al. 2001; Gallego and Virshup fibroblast cell lines indicate that peripheral tissues of 2007). mammals also have an autonomous capacity for circa- The proteins that constitute the core clock oscillator dian gene expression (Balsalobre et al. 1998; Yamazaki et regulate directly or indirectly the transcription of output al. 2000). The underlying circadian oscillators function genes, the expression products of which constitute the in a cell-autonomous and self-sustained manner, similar circadian transcriptome and proteome in every tissue to those operative in SCN neurons (Nagoshi et al. 2004; (Kornmann et al. 2001, 2007; Akhtar et al. 2002; Duffield Welsh et al. 2004; Liu et al. 2007). et al. 2002; Panda et al. 2002; Storch et al. 2002; McCar- Circadian rhythms appear to be generated by feedback thy et al. 2007; Miller et al. 2007). In the liver, for ex- ample, factors involved in processing and detoxification of nutrients have been found to be rhythmically ex- 3Corresponding author. E-MAIL [email protected]; FAX 41-22-379-68-68. pressed (Gachon et al. 2006). Interestingly, circadian ex- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.453808. pression of the majority of liver genes is tissue-specific, GENES & DEVELOPMENT 22:331–345 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org 331 Downloaded from genesdev.cshlp.org on August 4, 2008 - Published by Cold Spring Harbor Laboratory Press Reinke et al. and only a small fraction of these genes seems to be a (Fonjallaz et al. 1996). Other transcription factors, such direct target of the transcription factors that drive the as the orphan nuclear receptor REV-ERB␣, bind se- core oscillator (Panda et al. 2002). quences with a similar complexity (WAWNTRGGTCA) Insight into a transcriptional network such as the cir- and with similar affinities (Forman et al. 1994; L. Mar- cadian system requires the identification of all factors cacci and U. Schibler, unpubl.). Recognition sequences that are involved in its regulation. Gene expression is matching the PAR bZIP or REV-ERB␣ consensus se- primarily controlled by transcription factors, sequence- quences perfectly or with one mismatch exist statisti- specific DNA-binding proteins that bind to regulatory cally in random DNA once in every 2341 base pairs (bp) regions of genes and interact with the basic transcription (Fig. 1A). If the sequences of both complementary machinery to facilitate or repress transcription. The ex- strands are taken into consideration, at least one such pression and activity of transcription factors can, in prin- binding site should be found with a probability of >99% ciple, be regulated at the level of transcription, mRNA in ∼11,000 bp of random DNA (Fig. 1A). The number of stability, translation, protein stability, or by post-trans- well-conserved bases in the binding site of a eukaryotic lational mechanisms. Transcription factors whose ex- transcription factor is typically five to 10 (Wingender et pression is regulated at the level of mRNA accumulation al. 1996; Berg et al. 2004). The binding sequences for PAR can be identified by functional genomics strategies such bZIP proteins and REV-ERB␣ are, therefore, rather com- as microarray hybridization, serial analysis of gene ex- plex, and other, simpler binding sites like E-boxes (CAC pression, or massive parallel signature sequencing (Vel- GTG) are expected to be found with an even higher prob- culescu et al. 1995; Brenner et al. 2000; Panda et al. ability in random DNA. 2003). However, circadian transcription does not always This calculation prompted us to use random DNA result in circadian mRNA accumulation, due to a poten- fragments as probes for in vitro protein–DNA-binding tially long half-life of the mRNA. Moreover, all regula- experiments. Testing a sufficiently large number of ran- tory mechanisms that occur on the protein level—e.g., dom DNA probes should result in an unbiased display of phosphorylation, acetylation, glycosylation, farnesyla- most cellular DNA-binding activities. When using tion, ubiquitinylation, proteolytic cleavage, ligand bind- nuclear protein extracts harvested around the clock, this ing, multimerization, subcellular localization, etc.—es- experimental setup could then be used to screen for cir- cape this kind of analysis. Here we set out to circumvent cadian transcription factors. However, first we at- some of these shortcomings and developed a new tech- tempted to verify the validity of our calculations using nique, differential display of DNA-binding proteins bioinformatics tools. We used the Mersenne twister al- (DDDP), for the identification of circadian transcription gorithm for the generation of pseudo-random numbers factors based on their in vitro DNA-binding activity. Us- (Makoto and Takuji 1998) to create six random DNA ing this novel procedure, we were able to identify several libraries of 20,000 bp each. Statistically, one random well-established clock proteins as well as transcription DNA library of 20,000 bp contains 8.5 perfect or imper- factors that until now have not been implicated in cir- fect binding sites each for PAR bZIP proteins (RTTAYG cadian transcription in peripheral tissues. One of them, TAAY) and for REV-ERB␣ (WAWNTRGGTCA) and 4.4 heat-shock factor 1 (HSF1), displays highly circadian binding sites each for nuclear factor ␬B (NF-␬B, GG DNA-binding activity in the dark phase of the day. Maxi- GAMTTYCC) and serum response factor (SRF, CCA mal DNA binding coincides with the uptake of food and WATAWGG). When we inspected the in silico generated maximal core body temperature in the animals. Our re- libraries for binding sites for these transcription factors, sults suggest that every day the mammalian body goes the obtained frequencies came close to the calculated through a proteotoxic stress event that elicits the expres- ones (Fig. 1B). sion of cell-protective proteins.
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