Differential regulation of the SMN2 gene by individual HDAC proteins

Matthew C. Evans, Jonathan J. Cherry, Elliot Androphy

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)25-30
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume414
Issue number1
DOIs
StatePublished - Oct 14 2011
Externally publishedYes

Fingerprint

Histone Deacetylases
Spinal Muscular Atrophy
Genes
Motor Neurons
Neurons
Sequence Deletion
Muscular Diseases
Transcription
Luciferases
Neurodegenerative Diseases
Small Interfering RNA
Cause of Death
Exons
Proteins
Therapeutics
Polymerase Chain Reaction

Keywords

  • HDAC
  • Luciferase
  • RNAi
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Differential regulation of the SMN2 gene by individual HDAC proteins. / Evans, Matthew C.; Cherry, Jonathan J.; Androphy, Elliot.

In: Biochemical and Biophysical Research Communications, Vol. 414, No. 1, 14.10.2011, p. 25-30.

Research output: Contribution to journalArticle

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