The role of histone acetylation in SMN gene expression

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2005; 14(9):1171-82. DOI: 10.1093/hmg/ddi130
Source: PubMed


Increasing survival motor neuron 2 (SMN2) gene expression may be an effective strategy for the treatment of spinal muscular atrophy (SMA). Histone deacetylase (HDAC) inhibitors have been shown to increase SMN transcript and protein levels, but the specific role of histone acetylation in regulating SMN gene expression has not been explored. Using chromatin immunopreciptation, we investigated the levels of acetylated H3 and H4 histones and HDACs associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. We show that the SMN gene has a reproducible pattern of histone acetylation that is largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site has relatively high levels of histone acetylation, whereas regions further upstream or downstream have lower levels. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 levels increased at the region closest to the transcriptional start site, correlating with a 40-60% decrease in SMN transcript and protein levels. These data indicate that histone acetylation modulates SMN gene expression and that pharmacological manipulation of this epigenetic determinant is feasible. HDAC2, in particular, may be a future therapeutic target for SMA.

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    • "(b) The residue at position 65 is highly conserved among different species. Aim of this paper consists not only in describing this atypical case but also in reporting the clinical and molecular effects of the treatment with valproate (VPA) that was offered to the patient considering its potential of increasing SMN levels by an epigenetic mechanism [12] [13] [14]. Moreover, in order to interpret SMN molecular data into the correct frame, the expression of this protein in skin fibroblasts obtained from our patient was compared to that assessed in a group of sporadic ALS patients and healthy controls. "
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    ABSTRACT: Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.
    07/2014; 2014:216094. DOI:10.1155/2014/216094
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    • "Full-length Smn transcript levels were not increased in the brain, liver, and spinal cord of TSA treated delta 7 mice, however, there was a 1.5 fold increase in Smn protein levels in these tissues. It should be emphasized that the delta 7 model carries the human SMN2 transgene, which has been reported to be a direct target of TSA [11]. It still remains unclear whether the small increase in SMN protein levels is sufficiently capable to cause dramatic changes in phenotype. "
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    ABSTRACT: Spinal muscular atrophy is an autosomal recessive neuromuscular disease characterized by the progressive loss of alpha motor neurons in the spinal cord. Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. It is currently unclear whether TSA specifically targets the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-SMN mediated pathway. TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/- mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Of interest, TSA treatment did not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. In addition, no change in the level of Smn transcripts or protein in the brain or spinal cord of TSA-treated SMA model mice was observed. Furthermore, TSA did not increase Smn protein levels in the hind limb muscle, heart, or liver of Smn2B/- mice. We therefore conclude that TSA likely exerts its effects independent of the endogenous mouse Smn gene. As such, identification of the pathways regulated by TSA in the Smn2B/- mice could lead to the development of novel therapeutics for treating SMA.
    PLoS ONE 07/2014; 9(7):e101225. DOI:10.1371/journal.pone.0101225 · 3.23 Impact Factor
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    • "Janssen et al. (2010) found in ALS patients that HDAC2 expression was upregulated in motor cortex (in layers III–V, where upper motor neuron are located) and in spinal cord grey matter, particularly in the nuclei of motor neurons; they interpreted this result as a protective role of HDAC2 in ALS pathogenesis, although the mechanisms of this effect were not detailed. Regarding this issue, in an in vitro study Kernochan et al. (2005) reported that HDAC inhibition increased promoter activity of the survival motor neuron 2 gene, and this was associated with HDAC2 levels. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors.
    Frontiers in Cellular Neuroscience 12/2013; 7:243. DOI:10.3389/fncel.2013.00243 · 4.29 Impact Factor
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