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: 6.68). 06/2005; 14(9):1171-82. DOI: 10.1093/hmg/ddi130
Source: PubMed

ABSTRACT 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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    • "Compounds that have been shown to increase SMN2 expression include various histone deacetylase (HDAC) inhibitors, aclarubicin , indoprofen, splicing modifiers, a DcpS inhibitor, anti‐ terminators, proteasome inhibitors and inhibitors of multiple signalling pathways (Andreassi et al, 2001; Avila et al, 2007; Bowerman et al, 2010, 2012; Burnett et al, 2009; Chen et al, 2012; Farooq et al, 2009; Garbes et al, 2009; Hahnen et al, 2006; Hastings et al, 2009; Heier & DiDonato, 2009; Jarecki et al, 2005; Kernochan et al, 2005; Kwon et al, 2011; Lunn et al, 2004; Makhortova et al, 2011; Narver et al, 2008; Singh et al, 2008; Wolstencroft et al, 2005; Zhang et al, 2001, 2011). Because many of these activators are non‐specific and can have off‐target effects, their long‐term safety remains to be determined. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.
    EMBO Molecular Medicine 07/2013; 5(7). DOI:10.1002/emmm.201202305 · 8.25 Impact Factor
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    • "However, significant progress in the development of therapeutic strategies has been achieved. These include the following: (1) introducing the exogenous SMN1 gene by viral vectors (Foust et al., 2010; Passini et al., 2010; Valori et al., 2010; Dominguez et al., 2011); (2) increasing the SMN2 transcript and SMN protein by small-molecule drugs, such as histone deacetylase (HDAC) inhibitors (Kernochan et al., 2005; Avila et al., 2007; Garbes 1 "
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    ABSTRACT: In the search of the most efficacious antisense oligonucleotides (AO) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27) and PMO20 (-10, -29), complementary to SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon7 inclusion in vitro in spinal muscular atrophy (SMA) patients' fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further using a severe SMA mouse model. After a single intra cerebral ventricular (ICV) injection in neonatal mice, PMO25 increased the lifespan of severe SMA mice up to thirty-fold, with an average survival greater by three-fold than PMO18 at a dose of 20 µg/g and 2-fold at 40 µg/g. Exon7 inclusion was increased in the central nervous system (CNS) but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon7 inclusion both in the CNS and peripherally. Systemic administration of 10 µg/g of PMO25 conjugated to an octa-guanidine dendrimer (VMO25) increased the lifespan only two-fold in neonatal type I SMA mice, although prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice and (3) naked Morpholino oligomers are more efficient and safer than vivo-Morpholinos and have potential for future SMA clinical applications.
    Human gene therapy 01/2013; 24(3). DOI:10.1089/hum.2012.211 · 3.62 Impact Factor
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