Partitioning the circadian clock Yannan Xi and Danica Chen Science 345, 1122 (2014); DOI: 10.1126/science.1259601

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INSIGHTS | P E R S P E C T I V E S

ever, independent of the phase φ (see the figure, panel A). Thus, only a displacement of |Φ(k)| comes with a restoring force that establishes the Higgs mode at a finite frequency of 2ω∆. The collective Higgs mode appears only in a Lorentz-invariant relativistic theory (5), which is usually associated with highenergy particle physics. Obviously, the energy scale in superconductors is far below the level where relativistic effects play a noticeable role. Why, then, does the Higgs mode appear in this case? The reason is that the superconducting energy gap opens up in the spectrum of quasi-particles at the Fermi energy. Electrons with properties modified by their environment are termed quasi-particles in condensed matter physics, and the Fermi level denotes the energy limit up to the point that their quantum

“…the goal is to gain insight into strongly coupled low-energy excitations of complex matter by investigating their nonlinear dynamics…” states are occupied at zero temperature. Whereas the energy of quasi-particles in a normal metal depends linearly on their momentum in this region, it acquires a form analogous to the relativistic case in the superconducting state. The gap energy 2∆ = 2បω∆ plays the role of the rest mass of a particle-antiparticle pair (see the figure, panels B and C). Mathematically, this situation results in a formal identity of the Dirac Hamiltonian of Lorentz-invariant quantum theory and the BCS Hamiltonian used in the microscopic description of superconductivity developed by Bardeen, Cooper, and Schrieffer. The Higgs amplitude mode in superconductors does not come with a dipole moment. Therefore, it cannot couple to electromagnetic radiation directly. Nonetheless, using the formalism of Anderson’s pseudospins, Matsunaga et al. demonstrate that there exists a quadratic coupling between light and the Higgs mode that should result in resonant excitation at half the resonance frequency ω∆. To prove this prediction, Matsunaga et al. irradiated a superconducting NbN sample with intense light pulses with central frequencies from Department of Physics, University of Konstanz, 78457 Konstanz, Germany. E-mail: [email protected]

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0.3 to 0.8 THz (1.2 meV to 3.3 meV). Such energies correspond to the low superconducting transition temperature of 15 K in NbN. They fall into the terahertz spectral region, where both microwave and optical sources were once rather limited in amplitude. This problem has been solved recently with the development of tabletop terahertz sources based on femtosecond laser amplifiers. Optimized nonlinear conversion schemes now deliver unprecedented peak electric fields of terahertz light beyond 1 MV/cm (6) or even 100 MV/cm in the multi-terahertz region (7). Matsunaga et al. have observed two manifestations of the Higgs mode. First, they used a delayed broadband probe terahertz pulse to trace the dynamics of the order parameter (the superconducting energy gap). By careful measurements at different excitation frequencies and gap energies tuned by temperature, they convincingly demonstrate that the order parameter oscillates at twice the terahertz driving frequency, confirming their initial report (8). Second, in accordance with the theoretical prediction by the authors, the superconducting current induced in the sample should oscillate at the third harmonic of the excitation. The experiment clearly detects the terahertz field emitted by this current and its resonant character with respect to the superconducting gap energy. The results reported by Matsunaga et al. show that superconductors exhibit a strong “quantum” nonlinearity that originates from spontaneous breaking of symmetry and the resulting Higgs mode. Novel highfield terahertz technology is now actively used to study such quantum nonlinearities in solids (9–12). Quite generally, the goal is to gain insight into strongly coupled lowenergy excitations of complex matter by investigating their nonlinear dynamics with subcycle temporal resolution. This powerful new approach will continue to provide information that is inaccessible to conventional techniques based on linear analysis in the spectral domain. ■ REFERENCES

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

A. Cho, Science 337, 141 (2012). P. W. Anderson, Phys. Rev. 110, 827 (1958). Y. Nambu, Phys. Rev. 117, 648 (1960). R. Matsunaga et al., Science 345, 1145 (2014). M. Varma, J. Low Temp. Phys. 126, 901 (2002). J. Hebling, K.-L. Yeh, M. C. Hoffmann, B. Bartal, K. A. Nelson, J. Opt. Soc. Am. B 25, B6 (2008). A. Sell, A. Leitenstorfer, R. Huber, Opt. Lett. 33, 2767 (2008). R. Matsunaga et al., Phys. Rev. Lett. 111, 057002 (2013). S. Leinß et al., Phys. Rev. Lett. 101, 246401 (2008). B. Zaks, R. B. Liu, M. S. Sherwin, Nature 483, 580 (2012). F. Junginger et al., Phys. Rev. Lett. 109, 147403 (2012). O. Schubert et al., Nat. Photonics 8, 119 (2014).

10.1126/science.1257302

PHYSIOLOGY

Partitioning the circadian clock Sirtuin proteins divide control of the circadian gene expression and metabolism By Yannan Xi and Danica Chen

M

any physiological and behavioral events exhibit circadian rhythms, which are driven by internal circadian “clocks” that coordinate biological functions through the cyclic expression of at least 10 to 20% of the genes in any given tissue (1). The robustness of circadian rhythms deteriorates with age, and circadian perturbation results in the development of disorders such as diabetes, obesity, and brain dysfunction. Central to the mammalian clock is the complex of transcriptional regulatory proteins CLOCK and BMAL1 (2). A recent study by Masri et al. (3) proposes that SIRT1 and SIRT6, two sirtuin family members with nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase activity, regulate different facets of the CLOCK-BMAL1 network, and more surprisingly, control distinct classes of hepatic circadian genes. Partitioning circadian transcription by sirtuins suggests that in response to internal and external stimuli, circadian clocks selectively control sirtuindependent functions that are broadly associated with metabolism, stress resistance, inflammation, aging, and tissue regeneration, to provide organisms with plasticity to adapt to changing environments. The molecular basis of circadian rhythms is a transcriptional-translational feedback loop (2). The CLOCK-BMAL1 complex induces the expression of a number of genes, including the negative regulators of CLOCKBMAL1. CLOCK has acetyltransferase activity toward BMAL1 and histones (4), implicating chromatin remodeling in regulating circadian transcription. Acetylated BMAL1 appears more stable, and histone acetylation is associated with a relaxed chromatin state that is more permissive to gene transcription in eukaryotic cells. Masri et al. show that SIRT6, a histone deacetylase (5), associates with CLOCK-BMAL1 and reduces their chromatin binding. This finding provides a critical piece in the circadian clock sciencemag.org SCIENCE

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Circadian clock

Liver

Circadian transcription machinery

NAD+

CLOCK BMAL1 ?

NAD+ SREBP-1

SIRT1

SIRT6

DNA

Lipid and carbohydrate related genes

Peptide and cofactor genes

Metabolism

ILLUSTRATION: C. BICKEL/SCIENCE

Clock control. SIRT1 and SIRT6 regulate CLOCK-BMAL1 activity through different mechanisms and control distinct classes of hepatic circadian transcription and metabolic outputs.

puzzle. CLOCK-BMAL1 induces the expression of the gene Nampt, which encodes an enzyme that catalyzes a rate-limiting step in NAD+ biosynthesis (6, 7). The resulting increase in the cellular NAD+ concentrations activates SIRT1 and SIRT6. The deacetylase activity of SIRT1 counteracts CLOCK to drive the cyclic acetylation/deacetylation of BMAL1 and histones and orchestrate their function along the circadian cycle (8, 9). By contrast, SIRT6 activation reduces chromatin binding of CLOCK-BMAL1, tipping the balance toward the establishment of a repressive chromatin state. Masri et al. further took a systems biology approach to study hepatic circadian transcription regulated by SIRT1 and SIRT6. Ablation of the genes encoding SIRT1 or SIRT6 specifically in the mouse liver disrupted the expression of a large number of genes whose expression normally oscillates over a 24-hour period. This supports an essential Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA. E-mail: [email protected]

role for these sirtuins in regulating CLOCKBMAL1 activity. Surprisingly, the absence of hepatic SIRT1 or SIRT6 also caused a widespread oscillatory transcription of genes that was not observed in the livers of wildtype mice. Such large-scale de novo oscillating transcripts can also be triggered by nutritional challenge (10). These findings highlight the existence of numerous molecular pathways that influence circadian clocks, which may serve to systematically reprogram biological functions in a cell in response to changing environments. A key discovery of Masri et al. is that SIRT1 and SIRT6 regulate distinct classes of circadian genes (see the figure). Comparison of SIRT1- and SIRT6-dependent oscillating transcripts revealed remarkably little overlap. Genomic partitioning by sirtuins has physiological consequences. By integrating high-throughput circadian transcriptomics with circadian metabolomics data, Masri et al. found that SIRT1 and SIRT6 control different classes of circadian metabolites, reflecting their differential regulation of circadian transcription. Whereas SIRT1

SCIENCE sciencemag.org

preferentially controls peptide and cofactor metabolism, SIRT6 preferentially regulates fatty acid and carbohydrate metabolism. How does a deficiency in SIRT6 result in de novo rhythmic expression of a large number of transcripts and their related metabolites? Sterol regulatory element–binding protein 1 (SREBP-1), a transcription factor that controls fatty acid metabolism, may play an essential role. Masri et al. found that SREBP-1 binding sites are highly enriched at the promoters of circadian genes that respond to SIRT6. Circadian recruitment of SREBP-1 to the promoter of its target gene increased in the absence of SIRT6. The livers of SREBP-1–deficient mice displayed disrupted circadian expression of SREBP-1 target genes. How SIRT6 specifically influences the circadian chromatin recruitment of SREBP-1 remains an open question. The findings by Masri et al. have many important implications. The high-resolution systems approach used in their study, integrating circadian transcriptome and circadian metabolome, contrasts with current metabolic and physiological studies that sample gene expression and metabolites at one nonspecified time point, which may inevitably miss important information and generate inconsistency. The systems approach provides a new framework for future physiological studies. The discovery that circadian genes can be differentially controlled by sirtuins will also initiate further studies into signals that differentially activate sirtuins. This may yield new insights about the reorganization of circadian rhythms by environmental stimuli. A closer connection between sirtuins and circadian clocks is likely to enrich the understanding of both sirtuin biology and circadian regulation. Elucidating the circadian regulation by SIRT2 and SIRT7, two other sirtuin family members with nuclear localization and important physiological functions (11, 12), may provide insights into the etiology of metabolic diseases and aging. ■ REF ERENCES AND NOTES

1. S. Masri, P. Sassone-Corsi, Nat. Neurosci. 13, 1324 (2010). 2. C. Dibner, U. Schibler, U. Albrecht, Annu. Rev. Physiol. 72, 517 (2010). 3. S. Masri et al., Cell 158, 659 (2014). 4. M. Doi, J. Hirayama, P. Sassone-Corsi, Cell 125, 497 (2006). 5. E. Michishita et al., Nature 452, 492 (2008). 6. Y. Nakahata, S. Sahar, G. Astarita, M. Kaluzova, P. SassoneCorsi, Science 324, 654 (2009). 7. K. M. Ramsey et al., Science 324, 651 (2009). 8. G. Asher et al., Cell 134, 317 (2008). 9. Y. Nakahata et al., Cell 134, 329 (2008). 10. K. L. Eckel-Mahan et al., Cell 155, 1464 (2013). 11. H. S. Kim et al., Cancer Cell 20, 487 (2011). 12. J. Shin et al., Cell Reports 5, 654 (2013). ACKNOWL EDGMENTS

This work was supported by NIH (AG040990), Ellison Medical Foundation, and American Heart Association. 10.1126/science.1259601 5 SEP TEMBER 2014 • VOL 345 ISSUE 6201

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