Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism

Hatanaka, Fumiyuki; Matsubara, Chiaki; Myung, Jihwan; Yoritaka, Takashi; Kamimura, Naoko; Tsutsumi, Sadami; Kanai, Akinori; Suzuki, Yutaka; Aburatani, Hiroyuki; Sugano, Sumio; Takumi, Toru

doi:10.1016/j.neures.2011.07.226

Cited by 37 publications

(48 citation statements)

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“…Consistent with other published studies (6,7,19), our ChIP-seq results showed that the Gm129 gene has high affinity binding sites for CLOCK, BMAL1, and CRY1 in its promoter region (Fig. 1C).…”

Section: The Gm129 Gene Is a Direct Target Of Clock⅐bmal1⅐cry1supporting

confidence: 93%

“…Only one gene remains uncharacterized, gene model 129 (Gm129), which encodes a novel protein with no predicted functional domains. Gm129 is also implicated as a direct CLOCK⅐BMAL1 target gene based upon its strong transcriptional oscillation in liver in a additional independent BMAL1 ChIP-seq analysis using NIH3T3 and WI38 cell lines (6).…”

mentioning

confidence: 99%

“…To understand the direct targets of the CLOCK⅐BMAL1 complex and the molecular architecture of the circadian timing system, several studies have been conducted to identify the CLOCK⅐BMAL1 DNA-binding sites in vivo using ChIP-Seq analysis (6,7). It was reported that, in liver, BMAL1 rhythmically bound to ϳ2000 genomic targets (7).…”

mentioning

confidence: 99%

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Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Annayev

Adar

Chiou

et al. 2014

Journal of Biological Chemistry

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Background: Circadian gene expression in mammals is driven by rhythmic CLOCK⅐BMAL1 activities. Results: Gm129 binds to the CLOCK⅐BMAL1 complex on DNA and represses its transcriptional activator activity to regulate the circadian gene expression phase. Conclusion: Gm129 is a novel circadian clock modulator. Significance: The discovery of Gm129 reveals a new regulatory component of circadian gene expression.

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Section: The Gm129 Gene Is a Direct Target Of Clock⅐bmal1⅐cry1supporting

confidence: 93%

mentioning

confidence: 99%

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Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Annayev

Adar

Chiou

et al. 2014

Journal of Biological Chemistry

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“…the cistrome) of clock proteins across the circadian cycle. For example, thousands of DNAbinding sites in mouse liver are rhythmically occupied by BMAL1, including genes involved in sterol and TAG metabolic pathways (49,50) . Similarly, the circadian cistromes for REV-ERBα, nuclear receptor corepressor and histone deacetylase 3 overlap extensively and are enriched for genes involved in lipid metabolism (51)(52)(53) .…”

Section: Regulation Of Clock-controlled Genes Involved In Lipid Metabmentioning

confidence: 99%

Circadian regulation of lipid metabolism

Gooley

2016

Proc. Nutr. Soc.

135

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The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.

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“…One representative example is the E'-box (CACGTT), which participates in mammalian Per2 gene oscillation [20]. Recently, genome-wide analyses of BMAL1-binding sites by ChIP array or deep sequencing techniques also identified many E-box-like and non-canonical Ebox elements such as CCAATG, CATTGG, CATGTG, AACGTG, which extensively regulate clock-controlled genes [21,22]. These E-boxes can further form tandem repeats to regulate gene expression [22,23].…”

Section: Introductionmentioning

confidence: 99%

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Wang

et al. 2012

Cell Res

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CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle ARNT-like 1) are both transcription factors of the circadian core loop in mammals. Recently published mouse CLOCK-BMAL1 bHLH (basic helix-loop-helix)-PAS (period-ARNT-single-minded) complex structure sheds light on the mechanism for heterodimer formation, but the structural details of the protein-DNA recognition mechanisms remain elusive. Here we have elucidated the crystal structure of human CLOCK-BMAL1 bHLH domains bound to a canonical E-box DNA. We demonstrate that CLOCK and BMAL1 bHLH domains can be mutually selected, and that hydrogen-bonding networks mediate their E-box recognition. We identified a hydrophobic contact between BMAL1 Ile80 and a flanking thymine nucleotide, suggesting that CLOCK-BMAL1 actually reads 7-bp DNA and not the previously believed 6-bp DNA. To find potential non-canonical E-boxes that could be recognized by CLOCK-BMAL1, we constructed systematic single-nucleotide mutations on the E-box and measured their relevant affinities. We defined two non-canonical E-box patterns with high affinities, AACGTGA and CATGTGA, in which the flanking A7-T7′ base pair is indispensable for recognition. These results will help us to identify functional CLOCK-BMAL1-binding sites in vivo and to search for clock-controlled genes. Furthermore, we assessed the inhibitory role of potential phosphorylation sites in bHLH regions. We found that the phospho-mimicking mutation on BMAL1 Ser78 could efficiently block DNA binding as well as abolish normal circadian oscillation in cells. We propose that BMAL1 Ser78 should be a key residue mediating input signal-regulated transcriptional inhibition for external cues to entrain the circadian clock by kinase cascade.

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Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism

Abstract: 京都大学博士(医学) 氏名畠中史幸論文題目 Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism.

Cited by 37 publications

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Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Circadian regulation of lipid metabolism

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

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Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism

Abstract: 京都大学 博士(医学) 氏 名 畠中 史幸 論文題目 Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism.

Cited by 37 publications

References 0 publications

Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Circadian regulation of lipid metabolism

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Contact Info

Product

Resources

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Abstract: 京都大学博士(医学) 氏名畠中史幸論文題目 Genome-wide profiling of the core clock protein BMAL1 targets reveals strict relationship with metabolism.