Nott, A.; (2009) Nitric oxide induces chromatin remodelling in the developing central nervous system. Doctoral thesis , UCL (University College London).

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Abstract

The development of the nervous system is a complex task that involves precise connections between billions of neurons. This is achieved, at least in part, by the overproduction of neurons and the survival of a select few that compete for limited survival and growth promoting factors, such as neurotrophic factors. The neurotrophin brain-derived neurotrophin factor (BDNF) has been shown to play an important role in proliferation and differentiation of cortical neuronal precursors (Bartkowska et al 2007). Moreover, BDNF induces binding of the transcription factor CREB to gene promoters in a nitric oxide (NO)-dependent manner (Riccio et al 2006). NO positively regulates a large number of transcription factors and genes in the nervous system (Hemish et al 2003; Dhakshinamoorthy et al 2007). I have demonstrated that NO achieves this broad level of gene regulation by influencing chromatin remodelling. My data also show that NO accumulates within the nucleus of cortical neurons upon BDNF stimulation, thereby inducing Snitrosylation of a wide array of nuclear proteins. S-nitrosylation of histone deacetylase 2 (HDAC2) decreases its affinity for chromatin, leading to increased histone acetylation levels. This NO-dependent regulation of HDAC2 promotes changes in endogenous gene expression and affects the dendritic length of cortical neurons.

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