SUBTELOMERIC REPEAT EFFECT ON GENE EXPRESSION

端粒由两个离散的区域组成，端粒的末端阵列 简单的富含G的重复序列和包含更多 中等和高度重复的DNA的复杂排列。航站楼 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尚不清楚。 人类病理性面肩肩部肌营养不良症的研究 (FSHD)可能为这个问题提供见解。 FSHD是一种常染色体显性遗传性神经肌肉疾病，由缺失引起 D4Z4的完整拷贝，一个组织在 4Q上的一个大阵列。关键的FSHD基因尚不清楚。分析 D4Z4提示它参与了端粒的形成 抑制性异染色质。我们建议将D4Z4的缩写 阵列阻碍了抑制域的形成，并导致 激活邻近基因的表达。我们将使用两种方法 探讨D4Z4在转录调控中的这一拟议作用。 首先，我们将确定相邻基因的表达是否增加 通过比较FSHD和对照的mRNAs去除D4Z4 肌肉。其次，我们将通过以下方式直接测试D4Z4介导的抑制 确定D4Z4是否给予转录抑制 模式生物中的报告基因。 这些实验的结果将提供对这一角色的理解 亚端粒对相邻基因表达的影响。作为人类基因组 在端粒区域含有高度集中的基因， 亚端粒对转录的控制可能在 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.