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.
