title: The role of histone acetylation in SMN gene expression.
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.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kernochan
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Russo
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Woodling
authors.forename: Thanh N
authors.initials: TN
authors.lastname: Huynh
authors.forename: Amy M
authors.initials: AM
authors.lastname: Avila
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000187:drug effects; D018628:Gene Dosage; D015870:Gene Expression / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D055532:SMN Complex Proteins; D055540:Survival of Motor Neuron 2 Protein; D014158:Transcription, Genetic; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D000077337:Vorinostat; D014635:Valproic Acid; C004651:dipropylacetamide