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S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons


Brain-derived neurotrophic factor (BDNF) and other neurotrophins have a vital role in the development of the rat and mouse nervous system by influencing the expression of many specific genes that promote differentiation, cell survival, synapse formation and, later, synaptic plasticity1. Although nitric oxide (NO) is known to be an important mediator of BDNF signalling in neurons2, the mechanisms by which neurotrophins influence gene expression during development and plasticity remain largely unknown. Here we show that BDNF triggers NO synthesis and S-nitrosylation of histone deacetylase 2 (HDAC2) in neurons, resulting in changes to histone modifications and gene activation. S-nitrosylation of HDAC2 occurs at Cys 262 and Cys 274 and does not affect deacetylase activity. In contrast, nitrosylation of HDAC2 induces its release from chromatin, which increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes transcription. Notably, nitrosylation of HDAC2 in embryonic cortical neurons regulates dendritic growth and branching, possibly by the activation of CREB (cyclic-AMP-responsive-element-binding protein)-dependent genes. Thus, by stimulating NO production and S-nitrosylation of HDAC2, neurotrophic factors promote chromatin remodelling and the activation of genes that are associated with neuronal development.

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Figure 1: BDNF induces nuclear NO synthesis and S -nitrosylation of nuclear and cytoplasmic proteins.
Figure 2: BDNF induces S -nitrosylation of HDAC2 on Cys 262 and Cys 274.
Figure 3: S -nitrosylation of HDAC2 regulates its association with chromatin.
Figure 4: Neurotrophin-dependent S -nitrosylation of HDAC2 regulates dendritic growth.


  1. 1

    Huang, E. & Reichardt, L. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Riccio, A. et al. A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol. Cell 21, 283–294 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Huang, E. J. & Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003)

    CAS  Article  Google Scholar 

  6. 6

    Zweifel, L. S., Kuruvilla, R. & Ginty, D. D. Functions and mechanisms of retrograde neurotrophin signalling. Nature Rev. Neurosci. 6, 615–625 (2005)

    CAS  Article  Google Scholar 

  7. 7

    Zhang, J. & Snyder, S. H. Nitric oxide in the nervous system. Annu. Rev. Pharmacol. Toxicol. 35, 213–233 (1995)

    CAS  Article  Google Scholar 

  8. 8

    Boehning, D. & Snyder, S. H. Novel neural modulators. Annu. Rev. Neurosci. 26, 105–131 (2003)

    CAS  Article  Google Scholar 

  9. 9

    Stamler, J. S., Lamas, S. & Fang, F. C. Nitrosylation. the prototypic redox-based signaling mechanism. Cell 106, 675–683 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Hess, D. T., Matsumoto, A., Kim, S. O., Marshall, H. E. & Stamler, J. S. Protein S-nitrosylation: purview and parameters. Nature Rev. Mol. Cell Biol. 6, 150–166 (2005)

    CAS  Article  Google Scholar 

  11. 11

    Marshall, H. E., Hess, D. T. & Stamler, J. S. S-nitrosylation: Physiological regulation of NF-κB. Proc. Natl Acad. Sci. USA 101, 8841–8842 (2004)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Stroissnigg, H. et al. S-nitrosylation of microtubule-associated protein 1B mediates nitric-oxide-induced axon retraction. Nature Cell Biol. 9, 1035–1045 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Jaffrey, S. R. & Snyder, S. H. The biotin switch method for the detection of S-nitrosylated proteins. Sci. STKE 2001, PL1 (2001)

    CAS  PubMed  Google Scholar 

  14. 14

    Forrester, M. T., Foster, M. W. & Stamler, J. S. Assessment and application of the biotin switch technique for examining protein S-nitrosylation under conditions of pharmacologically induced oxidative stress. J. Biol. Chem. 282, 13977–13983 (2007)

    CAS  Article  Google Scholar 

  15. 15

    Whalen, E. J. et al. Regulation of β-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129, 511–522 (2007)

    CAS  Article  Google Scholar 

  16. 16

    Uehara, T. et al. S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513–517 (2006)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Hara, M. R. et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biol. 7, 665–674 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Hausladen, A., Privalle, C. T., Keng, T., DeAngelo, J. & Stamler, J. S. Nitrosative stress: activation of the transcription factor OxyR. Cell 86, 719–729 (1996)

    CAS  Article  Google Scholar 

  19. 19

    Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000)

    CAS  Article  Google Scholar 

  20. 20

    Berger, S. L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Wink, D. A. et al. Detection of S-nitrosothiols by fluorometric and colorimetric methods. Methods Enzymol. 301, 201–211 (1999)

    CAS  Article  Google Scholar 

  22. 22

    Haendeler, J. et al. Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nature Cell Biol. 4, 743–749 (2002)

    CAS  Article  Google Scholar 

  23. 23

    Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Mustafa, A. K. et al. Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of d-serine formation. Proc. Natl Acad. Sci. USA 104, 2950–2955 (2007)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Huang, Y. et al. S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron 46, 533–540 (2005)

    CAS  Article  Google Scholar 

  27. 27

    Redmond, L., Kashani, A. H. & Ghosh, A. Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron 34, 999–1010 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Bredt, D. S. & Snyder, S. H. Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 13, 301–313 (1994)

    CAS  Article  Google Scholar 

  29. 29

    Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Mallis, R. J., Buss, J. E. & Thomas, J. A. Oxidative modification of H-ras: S-thiolation and S-nitrosylation of reactive cysteines. Biochem. J. 355, 145–153 (2001)

    CAS  Article  Google Scholar 

  31. 31

    Huang, P. L., Dawson, T. M., Bredt, D. S., Snyder, S. H. & Fishman, M. C. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75, 1273–1286 (1993)

    CAS  Article  Google Scholar 

  32. 32

    Laherty, C. D. et al. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89, 349–356 (1997)

    CAS  Article  Google Scholar 

  33. 33

    Wegener, D., Wirsching, F., Riester, D. & Schwienhorst, A. A fluorogenic histone deacetylase assay well suited for high-throughput activity screening. Chem. Biol. 10, 61–68 (2003)

    CAS  Article  Google Scholar 

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We are grateful to D. D. Ginty, A. Lloyd, M. Raff and A. Saiardi for comments and to all members of the Riccio laboratory for discussion. We thank E. Seto for providing HDAC plasmids and A. Chittka for help with the purification of recombinant HDAC2. We also thank C. Andreassi for help with cell lines and molecular biology techniques. This work was supported by the Medical Research Council (MRC; grant G0500792), and the European Research Council (Marie Curie International Reintegration grant MIRG-CT-2005-016501). A.R. is a recipient of an MRC Career Development Fellowship (G117/533) and P.M.W. of an MRC Career Development Award.

Author Contributions A.N. performed most of the experiments, analysed the data and helped to write the manuscript. P.M.W. performed the HDAC activity assay and some of the biotin-switch and ChIP assays. J.D.R. provided the DAF-FM DA data and contributed to the analysis of dendritic growth. L.C. designed and tested the siRNAs and helped with the HDAC2 constructs. A.R., the senior author, designed the project, performed most of the ChIP assays, analysed the data, wrote the manuscript and provided financial support.

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Correspondence to Antonella Riccio.

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Nott, A., Watson, P., Robinson, J. et al. S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455, 411–415 (2008).

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