SUBTELOMERIC REPEAT EFFECT ON GENE EXPRESSION

端粒由两个离散的区域组成，一个是端粒的末端阵列， 一个简单的富含G重复序列和一个相邻的亚端粒区， 中间和高度重复的DNA的复杂排列。 终端 富含G的序列是染色体完整性和稳定性所必需的。 亚端粒在细胞过程中的功能是未知的。 人类面肩肱型肌营养不良症的研究 （FSHD）可以为这个问题提供见解。 FSHD是一种常染色体显性遗传的神经肌肉疾病， D4Z4是一种亚端粒串联重复序列， 4q上的一个大数组。 关键的FSHD基因是未知的。 分析 D4Z4表明它参与端粒的形成。 抑制性异染色质 我们建议缩短D4Z4 阵列损害阻遏结构域的形成， 激活邻近基因的表达。 我们将使用两种方法 探索D4Z4在转录调控中的作用。 首先，我们将确定相邻基因的表达是否增加 通过比较来自FSHD和对照的mRNA， 肌肉. 第二，我们将直接测试D4Z4介导的抑制， 确定D4Z4是否赋予转录抑制至转录抑制因子。 模式生物中的报告基因。 从这些实验的结果将提供一个了解的作用 对相邻基因表达的影响。 作为人类基因组 在端粒区域含有高浓度的基因， 转录的亚端粒控制可能是重要的， 其他疾病表型的发病机制。

Telomeres are composed of two discrete regions, a terminal array of a simple G-rich repeat and an adjacent subtelomeric region containing more complex arrangements of middle and highly repetitive DNA. The terminal G-rich sequences are required for chromosomal integrity and stability. The function of the subtelomere in cellular processes is unknown. Studies of the human disease facioscapulohumeral muscular dystrophy (FSHD) may provide insights into this question. FSHD is an autosomal dominant neuromuscular disease caused by deletion of integral copies of D4Z4, a subtelomeric tandem repeat organized in a large array on 4q. The critical FSHD gene is unknown. Analysis of D4Z4 suggests that it participates in the formation of telomeric repressive heterochromatin. We propose that shortening of the D4Z4 array impairs formation of a domain of repression and results in activation of neighboring gene expression. We will use two approaches to explore this proposed role for D4Z4 in transcriptional regulation. First, we will determine whether expression of adjacent genes increases upon removal of D4Z4 through a comparison of mRNAs from FSHD and control muscle. Second, we will directly test for D4Z4 mediated repression by determining whether D4Z4 confers transcriptional repression to a reporter gene in a model organism. Results from these experiments will provide an understanding of the role of the subtelomere on adjacent gene expression. As the human genome contains a high concentration of genes in telomeric regions, subtelomeric control of transcription may be important in the pathogenesis of other disease phenotypes.