High‐resolution analysis of DNaseI‐hypersensitive sites in a muscular dystrophy‐linked subtelomeric region of 4q

Abstract

DNaseI hypersensitive (DH) sites are associated with nucleosome‐free chromatin subregions often in promoters, enhancers, and locus control regions. We used DNase‐chip to examine DH sites in two regions of special interest to facioscapulohumeral muscular dystrophy (FSHD). This dominant disease remains enigmatic even after five expression microarray studies. Custom tiling arrays for this study represented 4q35.2, including D4Z4 arrays of tandem 3.3‐kb repeats whose contraction is linked to FSHD, and 10q26.3 with its almost identical, but phenotypically neutral, D4Z4 arrays. In the center of the 4‐Mb 4q35.2, there was a low density of DH sites, consistent with its low density of known genes. Some 4q35.2 or 10q26.3 genes in three FSHD and three control myoblast cell populations had DH sites just in 5'gene regions (e.g., FRG1), and others had DH sites at many intragenic positions (e.g., FAT and INPP5A). DH sites were observed in sequences corresponding to hypothetical proteins (C10orf92 and C10orf93) and in subregions far from known genes. The 4q‐specific nature of FSHD is likely to be due to differences between the chromatin landscape of 4q35.2 and 10q26.3 that make only 4q D4Z4 contractions pathogenic. Our data illustrate the large‐scale differences in chromatin in these subtelomeric regions and suggest where to look for FSHD‐relevant long‐distance chromatin interactions. (Supported in part by NIH Grant NS048859)