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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi130
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Published by Oxford University Press 2005
Received January 28, 2005
Revised March 8, 2005
Accepted March 10, 2005

Article

The role of histone acetylation in SMN gene expression

Lauren E. Kernochan 1, Melissa L. Russo 1, Nathaniel S. Woodling 1, Thanh N. Huynh 1, Amy M. Avila 1, Kenneth H. Fischbeck 1, and Charlotte J. Sumner 2*

1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA
2 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA; Neurogenetics Branch, NINDS, NIH, Building 35, Room 2A-1010, 35 Convent Drive, Bethesda, MD 20892

* To whom correspondence should be addressed.
Charlotte J. Sumner, E-mail: sumnerc{at}ninds.nih.gov


  Abstract

Increasing survival motor neuron 2 (SMN2) gene expression may be an effective strategy for the treatment of spinal muscular atrophy. Histone deacetylase 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 histone deacetylases (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 histone deacetylase inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a two-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 spinal muscular atrophy.


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