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Genome-Wide Profiling of the Core Clock Protein BMAL1 Targets

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Genome-Wide Profiling of the Core Clock Protein BMAL1 Targets MOLECULAR AND CELLULAR BIOLOGY, Dec. 2010, p. 5636–5648 Vol. 30, No. 24 0270-7306/10/$12.00 doi:10.1128/MCB.00781-10 Copyright © 2010, American Society for Microbiology. All Rights Reserved. Genome-Wide Profiling of the Core Clock Protein BMAL1 Targets Reveals a Strict Relationship with Metabolismᰔ Fumiyuki Hatanaka,1,2,3 Chiaki Matsubara,1 Jihwan Myung,1,3,4 Takashi Yoritaka,3 Naoko Kamimura,5 Shuichi Tsutsumi,5 Akinori Kanai,6 Yutaka Suzuki,6 Paolo Sassone-Corsi,7 Hiroyuki Aburatani,5 Sumio Sugano,6 and Toru Takumi1,2,3,8* Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan1;GraduateSchoolofMedicine,KyotoUniversity,Sakyo,Kyoto606-8501, Downloaded from Japan2;GraduateSchoolofBiomedicalSciences,HiroshimaUniversity,Minami,Hiroshima734-8553,Japan3; Graduate School of Biostudies, Kyoto University, Sakyo, Kyoto 606-8501, Japan4; Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Meguro, Tokyo 153-8904, Japan5;DepartmentofMedicalGenomeSciences,GraduateSchoolofFrontierSciences,Universityof Tokyo, Minato, Tokyo 108-8639, Japan6; Department of Pharmacology, School of Medicine, University of California, Irvine, California 926977; and JST, CREST, 102-0075 Tokyo, Japan8 Received 8 July 2010/Returned for modification 4 August 2010/Accepted 14 September 2010 http://mcb.asm.org/ Circadian rhythms are common to most organisms and govern much of homeostasis and physiology. Since a significant fraction of the mammalian genome is controlled by the clock machinery, understanding the genome-wide signaling and epigenetic basis of circadian gene expression is essential. BMAL1 is a critical circadian transcription factor that regulates genes via E-box elements in their promoters. We used multiple high-throughput approaches, including chromatin immunoprecipitation-based systematic analyses and DNA microarrays combined with bioinformatics, to generate genome-wide profiles of BMAL1 target genes. We reveal that, in addition to E-boxes, the CCAATG element contributes to elicit robust circadian expression. BMAL1 occupancy is found in more than 150 sites, including all known clock genes. Importantly, a significant on August 6, 2012 by HIROSHIMA UNIVERSITY proportion of BMAL1 targets include genes that encode central regulators of metabolic processes. The database generated in this study constitutes a useful resource to decipher the network of circadian gene control and its intimate links with several fundamental physiological functions. Many physiological phenomena in almost all of organisms (30). These notions indicate that global mechanisms of gene are regulated in a circadian manner. This is possible through expression, specifically chromatin remodeling (23), must oper- the function of an intrinsic biological clock or pacemaker. The ate to accommodate these genome-wide oscillations. circadian clock operates independently of external cues, but it The transcriptional-translational feedback loops that consti- has remarkable plasticity and so can adapt to changing envi- tute the core circadian oscillator have been dissected. At the ronmental conditions. Dysfunctions of the circadian clock are core of the circadian machinery lies the BMAL1 protein, a associated with a wide variety of disorders in humans, includ- basic helix-loop-helix (bHLH) type transcription factor that ing insomnia, depression, cardiovascular disorders, and cancer forms hetero-complexes with either CLOCK or NPAS2, two (13, 35, 40). The central circadian pacemaker in mammals is other bHLH nuclear activators with different tissue distribu- located within the suprachiasmatic nucleus (SCN) in the ante- tions (10, 50). These dimers activate the transcription of clock- rior hypothalamus (13). controlled genes (CCGs) and of genes encoding other ele- A critical advance in the field has been the discovery of ments of the clock machinery, specifically the Per and Cry circadian clocks present in peripheral tissues and in cultured genes. Once synthesized, PERs and CRYs inhibit CLOCK/ cells (13). The SCN appears to function by orchestrating pe- BMAL1 activation potential, resulting in the downregulation ripheral clocks (37), likely by using a specific group of humoral of their own transcription (31). The circadian transcription of signals as synchronizing elements, including glucocorticoids the Bmal1 gene is itself regulated by nuclear receptors posi- and retinoic acid (12). This complex network relies on a highly tively by RORs and negatively by REV-ERBs (2, 29, 36). controlled system of gene expression, in which interlocked Importantly, Bmal1-deficent mice exhibit arrhythmic locomo- transcriptional-translational feedback loops operate (20, 31, 50). Also, microarray studies have revealed that ca. 10 to 15% tor activity in constant darkness, a unique case as single-gene of all transcripts in different tissues display circadian oscillation ablation among all clock genes (5), indicating that BMAL1 is (3, 9, 26, 38). More recent data suggest that the expression of indeed indispensable to generate circadian gene expression. as much as 50% of all genes oscillates in a circadian manner DNA microarray analyses in both SCN and peripheral tis- sues (26, 38, 46) and further bioinformatic analyses determined that circadian transcription may be elicited through three pro- * Corresponding author. Mailing address: Laboratory of Integrative moter elements (E-box, RORE, and DBPE) (47, 52). Among Bioscience, Graduate School of Biomedical Sciences, Hiroshima Univer- these, the E-box appears to play a major role as it is highly sity, 1-2-3 Kasumi, Minami, Hiroshima 734-8553, Japan. Phone: 81-82- 257-5115. Fax: 81-82-257-5119. E-mail: [email protected]. abundant in the mammalian genome and responsible in driving ᰔ Published ahead of print on 11 October 2010 . the expression of most CCGs (47). However, with the excep- 5636 VOL. 30, 2010 PROFILES OF CORE CLOCK PROTEIN BMAL1 TARGETS 5637 tion of a limited number of individually studied genes (11, 24), The DNA was recovered by phenol-chloroform-isoamyl alcohol (25:24:1) extrac- the extent of BMAL1-mediated control of circadian transcrip- tion and ethanol precipitation. Sequencing. Bmal1-bound DNA was purified by SDS-PAGE to obtain 150- to tion at a genome-wide level remains unknown. 250-bp fragments and sequenced on an Illumina GA sequencer. About 15,000 to We describe here results obtained by a systematic analysis 20,000 clusters were generated per “tile,” and 26 cycles of the sequencing reac- using a chromatin immunoprecipitation (ChIP)-based technol- tions were performed according to the manufacturer’s instructions. ogy and a genome-wide microarray. We have applied ChIP- Tiling array. ChIP and control samples were amplified by two cycles of in vitro on-chip (ChIP-chip) (17) and ChIP coupled with ultra-high- transcription and hybridized on separate Affymetrix human promoter 1.0 oligo- nucleotide tiling arrays as described previously (49). Enrichment values (ChIP/ throughput DNA sequencing (ChIP-seq) methods (4, 7, 15, 33) control) were calculated with the MAT algorithm as described previously to reveal BMAL1 target genes at a whole genome level. All (16, 49). known CCGs driven by E-boxes are present in our systematic Data processing. The obtained sequences were mapped onto mouse genomic ChIP results and the profiling of BMAL1 targets reveals strict sequences (mm9 as of UCSC Genome Browser [http://genome.ucsc.edu/]) using the sequence alignment program Eland. Unmapped or redundantly mapped Downloaded from relationship with metabolism. Our analysis has revealed unex- sequences were removed from the data set. For uniquely mapped sequences, pected features of circadian gene control and constitutes a relative positions to RefSeq genes were calculated based on the respective valuable resource to study the link between clock control and genomic coordinates. Genomic coordinates of exons and other information of cellular metabolism. the RefSeq transcripts are as described in mm9 as of UCSC Genome Browser. GO (as of 14 June 2007) and KEGG (release 42) terms were associated with RefSeq genes by using loc2go (as of 14 June 2007) using NCBI Entrez Gene database (http://www.ncbi.nlm.nih.gov/sites/entrez?dbϭgene). Details and ratio- MATERIALS AND METHODS nalization of the procedure were as described previously (43). Cell culture. NIH 3T3 and WI38 cells were maintained at 37°C and 5% CO2 Motif analysis. MEME (for Multiple Em for Motif Elicitation) with default in Dulbecco modified Eagle medium (Nacalai Tesque, Kyoto, Japan) supple- parameters was used to identify statistically overrepresented consensus motifs http://mcb.asm.org/ mented with 10% newborn bovine serum (NBS; ICN Biomedicals, Inc.) and within the inferred binding sites. antibiotics. Quantitative real-time RT-PCR. Each quantitative real-time reverse transcrip- Animals. Male BALB/c mice purchased 5 weeks postpartum from Japan SLC tion-PCR (RT-PCR) was performed using the ABI Prism 7900HT sequence (Hamamatsu, Japan) were exposed to 2 weeks of 12:12 light-dark (LD) cycles detection system as described previously (25), The PCR primers were designed and then kept in complete darkness as a continuation of the dark phase of the with Primer Express software (Applied Biosystems), and the sequences of the last LD cycle. Liver mRNA levels were examined in the third dark-dark (DD) primers are shown in Table S5 at the URL in “Antibody,” above. The reaction cycle. Adult Bmal1Ϫ/Ϫ (5) and wild-type mice were kept in a LD cycle and killed was first incubated at 50°C for 2 min and then at 95°C
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