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

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/nature07238

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