title: Differential regulation of the SMN2 gene by individual HDAC proteins.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. We sought to identify the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 genes. We used quantitative PCR to determine the effects shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Evans
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cherry
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
mesh_terms: D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D008156:Luciferases; D012319:RNA Polymerase II; D006655:Histone Deacetylases