S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration

Abstract

Dynamic epigenetic modifications play a key role in mediating the expression of genes required for neuronal development. We previously identified nitric oxide (NO) as a signaling molecule that mediates S-nitrosylation of histone deacetylase 2 (HDAC2) and epigenetic changes in neurons. Here, we show that HDAC2 nitrosylation regulates neuronal radial migration during cortical development. Bead-array analysis performed in the developing cortex revealed that brahma (Brm), a subunit of the ATP-dependent chromatin-remodeling complex BRG/brahma-associated factor, is one of the genes regulated by S-nitrosylation of HDAC2. In the cortex, expression of a mutant form of HDAC2 that cannot be nitrosylated dramatically inhibits Brm expression. Our study identifies NO and HDAC2 nitrosylation as part of a signaling pathway that regulates cortical development and the expression of Brm in neurons.neural development | transcription | nitric oxide synthase | polar morphology | schizophrenia N euronal development relies on a number of sequential events whereby a pool of undifferentiated embryonic progenitor cells gives rise to a variety of highly specialized postmitotic neurons and glia. In the cortex, neuronal and glial cells derive from multipotent neural progenitor cells (NPCs) generated in the ventricular zone (VZ) of the developing brain. NPCs either undergo self-renewal or exit the cell cycle, differentiate into postmitotic neurons, and migrate to the external layers of the cortex (1). Cortical layers are formed between embryonic day 11 (E11) and E18 in an inside-out manner with deep layers formed first, followed by the more superficial layers, and the formation depends on radial neuron migration. Extracellular cues that regulate this process include brain-derived neurotrophic factor (BDNF) (2). Although BDNF and TrkB signaling are not required for neuronal survival in the embryonic cortex, they have been implicated in the regulation of NPC proliferation (3) and radial and tangential neuronal migration (2).In addition to the coordinated expression of nuclear factors that regulate, first, neurogenesis and neuronal migration and, later, promote gliogenesis, epigenetic modifications of both DNA and histones represent fundamental mechanisms by which neurons adapt their transcriptional response to corticogenic cues (4). Histone acetylases and deacetylases (HDACs) are nuclear enzymes that maintain chromatin acetylation in balance, thereby contributing to both transcriptional activation and repression. All HDACs identified so far are present in the nervous system and are often developmentally regulated. For example, the highly homologous HDAC1 and HDAC2 are detected at different stages of neuronal development, with HDAC1 confined to neural stem cells and glia and HDAC2 predominantly expressed in postmitotic neuroblasts and differentiated neurons (5).Although it is now established that many posttranslational modifications of HDACs impact on their activity, there is little evidence directly linking extrinsic stimuli to changes of nucle...

A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development

“…Recent work from our lab (Nott et al., 2008, Nott et al., 2013) and others (Hagelkruys et al., 2014, Hagelkruys et al., 2015) demonstrated that the class I histone deacetylases HDAC1 and HDAC2 control the expression of genes necessary for neuronal development. Class I HDACs do not bind DNA directly and are found within large multiprotein complexes that confer target specificity (Haberland et al., 2009).…”

HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex

“…The chromatin function of HDAC2 can be negatively regulated following a posttranslational modification by nitric oxide, called S -nitrosylation [24]. HDAC2 nitrosylation has been shown to have a role in regulating both cortical development and memory formation [22, 24, 25]. Interestingly, neuronal nitric oxide synthase (nNOS), an enzyme which provides a major source of nitric oxide in neurons, is highly expressed specifically in interneuron cell populations in the adult mouse cortex [26, 27].…”

A Novel Suppressive Effect of Alcohol Dehydrogenase 5 in Neuronal Differentiation

“…ADH5 neuronal differentiation antagonism seems to depend on ADH5 catalytic activity. It was reported that S-nitrosation of HDAC2 mediates neurotrophin-dependent chromatin remodeling and the activation of neuronal development genes (7,30), and likewise HDAC inhibition is able to promote neuronal differentiation (31). Our study reveals that ADH5 serves as a denitrosation enzyme for HDAC2, and programmed down-regulation of AHD5 may lead to a derepression of HDAC2 by increasing its S-nitrosation, which consequently facilitates specific gene expression resulting in neuronal differentiation and development.…”

“…in denitrosating both S-nitrosoglutathione and specific S-nitrosated proteins (11,28,29). Considering that S-nitrosation of HDAC2 is required for epigenetic activation of neuronal differentiation-associated genes (7,30), we hypothesize that ADH5 may antagonize neurogenesis by denitrosating HDAC2. To test this, we first investigated whether S-nitrosated HDAC2 is a target of ADH5.…”