Regulation of the survival motor neuron gene

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是婴儿死亡的最常见遗传原因。这种疾病是由运动神经元生存基因1（SMN1）突变引起的。所有患者都保留了第二个基因拷贝（SMN2），该基因产生的SMN蛋白量不足以完全补偿SMN1的损失。SMA的一种有前景的治疗策略是通过增加SMN2基因表达来增加SMN蛋白水平。在我们实验室和其他小组所做的初步工作表明，组蛋白去乙酰化酶抑制剂可以增加SMN水平在体外。然而，这些化合物的具体作用机制以及调节SMN 2基因表达的基本机制目前尚不清楚。我们的目标是了解调节SMN2基因表达的机制，以推进SMA的治疗。我们假设SMN2基因部分受组蛋白的乙酰化状态和DNA的甲基化状态调节，这些状态与SMN2启动子内的顺式和反式作用因子协同作用，并且操纵这些决定因素可导致人类细胞中SMN水平增加。我们计划通过以下三个具体目标来验证我们的假设：具体目标1：描述组蛋白乙酰化和DNA甲基化在SMN基因表达调控中的作用。具体目标二：鉴定与表观遗传决定簇共同调控SMN基因表达的转录因子和SMN启动子元件。具体目标3：表征SMA患者外周血细胞中的基线SMN蛋白水平，并检测调节SMN基因表达的药理学化合物在体外增加这些细胞中SMN蛋白水平的能力。

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.