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Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology

Abstract

Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1,2,3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4,5,6,7. The nuclear receptor corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (Hdac3)8. Lack of Ncor1 is incompatible with life, and hence it is unknown whether Ncor1, and particularly its regulation of Hdac3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the Ncor1–Hdac3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1–Hdac3 complex in vivo does not lead to sustained increases in known catabolic genes, but instead significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.

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Figure 1: Ncor1–Hdac3 regulates peripheral clock and circadian physiology.
Figure 2: DADm mice exhibit increased energy expenditure.
Figure 3: DADm mice are resistant to diet-induced obesity.
Figure 4: Activation of Hdac3 by Ncor1 regulates circadian metabolic gene expression in the liver.

References

  1. 1

    Ripperger, J. A. & Schibler, U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nature Genet. 38, 369–374 (2006)

    CAS  Article  Google Scholar 

  2. 2

    Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Etchegaray, J. P., Lee, C., Wade, P. A. & Reppert, S. M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2003)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004)

    Article  Google Scholar 

  6. 6

    Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Liu, C., Li, S., Liu, T., Borjigin, J. & Lin, J. D. Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Nature 447, 477–481 (2007)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001)

    CAS  Article  Google Scholar 

  9. 9

    Jepsen, K. et al. Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102, 753–763 (2000)

    CAS  Article  Google Scholar 

  10. 10

    Gachon, F., Nagoshi, E., Brown, S. A., Ripperger, J. & Schibler, U. The mammalian circadian timing system: from gene expression to physiology. Chromosoma 113, 103–112 (2004)

    Article  Google Scholar 

  11. 11

    Lowrey, P. L. & Takahashi, J. S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407–441 (2004)

    CAS  Article  Google Scholar 

  12. 12

    Schultz, T. F. & Kay, S. A. Circadian clocks in daily and seasonal control of development. Science 301, 326–328 (2003)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Annu. Rev. Physiol. 63, 647–676 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Desvergne, B., Michalik, L. & Wahli, W. Transcriptional regulation of metabolism. Physiol. Rev. 86, 465–514 (2006)

    CAS  Article  Google Scholar 

  16. 16

    Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Yin, L. et al. Rev-erbaα, a heme sensor that coordinates metabolic and circadian pathways. Science 318, 1786–1789 (2007)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Ishizuka, T. & Lazar, M. A. The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor. Mol. Endocrinol. 19, 1443–1451 (2005)

    CAS  Article  Google Scholar 

  19. 19

    Bhaskara, S. et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 30, 61–72 (2008)

    CAS  Article  Google Scholar 

  20. 20

    Yin, L. & Lazar, M. A. The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol. Endocrinol. 19, 1452–1459 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002)

    CAS  Article  Google Scholar 

  22. 22

    Liu, A. C. et al. Redundant function of REV-ERBα and β and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet. 4, e1000023 (2008)

    Article  Google Scholar 

  23. 23

    Yu, C. et al. The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor γ transcriptional activity and repress 3T3–L1 adipogenesis. J. Biol. Chem. 280, 13600–13605 (2005)

    CAS  Article  Google Scholar 

  24. 24

    Knutson, S. K. et al. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 27, 1017–1028 (2008)

    CAS  Article  Google Scholar 

  25. 25

    Matsuzaka, T. et al. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nature Med. 13, 1193–1202 (2007)

    CAS  Article  Google Scholar 

  26. 26

    Jansen, M. S., Cook, G. A., Song, S. & Park, E. A. Thyroid hormone regulates carnitine palmitoyltransferase Iα gene expression through elements in the promoter and first intron. J. Biol. Chem. 275, 34989–34997 (2000)

    CAS  Article  Google Scholar 

  27. 27

    Leone, T. C. et al. The human medium chain Acyl-CoA dehydrogenase gene promoter consists of a complex arrangement of nuclear receptor response elements and Sp1 binding sites. J. Biol. Chem. 270, 16308–16314 (1995)

    CAS  Article  Google Scholar 

  28. 28

    Martino, T. A. et al. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1675–R1683 (2008)

    CAS  Article  Google Scholar 

  29. 29

    Fuller, P. M., Lu, J. & Saper, C. B. Differential rescue of light- and food-entrainable circadian rhythms. Science 320, 1074–1077 (2008)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Ramsey, K. M., Marcheva, B., Kohsaka, A. & Bass, J. The clockwork of metabolism. Annu. Rev. Nutr. 27, 219–240 (2007)

    CAS  Article  Google Scholar 

  31. 31

    Kapfhamer, D. et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nature Genet. 32, 290–295 (2002)

    CAS  Article  Google Scholar 

  32. 32

    Qi, Y. et al. Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes 55, 3083–3090 (2006)

    CAS  Article  Google Scholar 

  33. 33

    Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998)

    CAS  Article  Google Scholar 

  34. 34

    Ishizuka, T. & Lazar, M. A. The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol. Cell. Biol. 23, 5122–5131 (2003)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank W. Pear for providing EIIa-Cre C57BL/6 mice, G. Barnes and J. Rusche for providing MS-275, P. White and J. Tobias for bioinformatics assistance, and L. Yin, S.-H. You, M. Qatanani and other members of the Lazar laboratory for helpful discussions. We also thank J. Richa and The Transgenic Mouse Core, H. Collins and the Radioimmunoassay/Biomarkers Core, R. Dhir and the Metabolic Phenotyping Core of the Penn Diabetes and Endocrinology Research Center (DK19525), H. Fu and the Mouse Embryonic Stem Cell Core (DK49210) and the Morphology Core of the Center for Molecular Studies in Digestive and Liver Disease (DK50306 and DK49210) for consultation and services. This work was supported by National Institutes of Health grant DK43806 (to M.A.L.), and T.A. was supported by a National Research Training Grant in Developmental Biology.

Author Contributions T.A., M.B., K.H.K., R.S.A. and M.A.L. designed the research, T.A., K.M., K.L., A.A.-A., S.E.M. and J.A. acquired the data, T.A., A.A.-A., S.E.M., M.B., R.S.A. and M.A.L. analysed and interpreted the data, and T.A. and M.A.L. drafted the manuscript.

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Correspondence to Mitchell A. Lazar.

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Alenghat, T., Meyers, K., Mullican, S. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008). https://doi.org/10.1038/nature07541

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