Regulation of the survival motor neuron gene

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DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is the most common inherited cause of infant mortality. The disease is caused by mutations in the survival motor neuron 1 (SMN1) gene. All patients retain a second copy of the gene (SMN2) that produces insufficient quantities of SMN protein to fully compensate for the loss of SMN1. One promising therapeutic strategy for SMA is to augment SMN protein levels by increasing SMN2 gene expression. Preliminary work done in our laboratory and by other groups indicates that histone deacetylase inhibitors can increase SMN levels in vitro. However, the specific mechanism of action of these compounds and the fundamental mechanisms that regulate SMN2 gene expression are currently unknown. Our goal is to understand the mechanisms that regulate SMN2 gene expression in order to advance therapy for SMA. We hypothesize that the SMN2 gene is regulated, in part, by the acetylation state of histones and the methylation state of DNA acting in concert with cis- and trans-acting factors within the SMN2 promoter and that manipulation of these determinants can lead to increased SMN levels in human cells. We plan to test our hypothesis by pursuing the following three Specific Aims: Specific Aim 1: To characterize the role of histone acetylation and DNA methylation in SMN gene expression regulation. Specific Aim 2: To identify transcription factors and SMN promoter elements that act in concert with epigenetic determinants to regulate SMN gene expression. Specific Aim 3: To characterize baseline SMN protein levels in peripheral blood cells of SMA patients and to test the ability of pharmacological compounds that modulate SMN gene expression to increase SMN protein levels in these cells in vitro.