Nucleic Acids Research Advance Access published online on October 9, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp833
Gene Regulation, Chromatin and Epigenetics |
DNaseI hypersensitivity at gene-poor, FSH dystrophy-linked 4q35.2
1Human Genetics Program and Department of Biochemistry and Tulane Cancer Center, Tulane Medical School, New Orleans, LA 70112, 2University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 and 3Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
*To whom correspondence should be addressed. Tel: +1 504-988-2449; Fax: +1 504-584-1763; Email: ehrlich{at}tulane.edu Correspondence may also be addressed to Greg Crawford. Tel: +1 919-684-8196; Fax: +1 919-668-0795; Email: greg.crawford{at}duke.edu
Received August 12, 2009. Revised September 15, 2009. Accepted September 18, 2009.
A subtelomeric region, 4q35.2, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant disease thought to involve local pathogenic changes in chromatin. FSHD patients have too few copies of a tandem 3.3-kb repeat (D4Z4) at 4q35.2. No phenotype is associated with having few copies of an almost identical repeat at 10q26.3. Standard expression analyses have not given definitive answers as to the genes involved. To investigate the pathogenic effects of short D4Z4 arrays on gene expression in the very gene-poor 4q35.2 and to find chromatin landmarks there for transcription control, unannotated genes and chromatin structure, we mapped DNaseI-hypersensitive (DH) sites in FSHD and control myoblasts. Using custom tiling arrays (DNase-chip), we found unexpectedly many DH sites in the two large gene deserts in this 4-Mb region. One site was seen preferentially in FSHD myoblasts. Several others were mapped >0.7 Mb from genes known to be active in the muscle lineage and were also observed in cultured fibroblasts, but not in lymphoid, myeloid or hepatic cells. Their selective occurrence in cells derived from mesoderm suggests functionality. Our findings indicate that the gene desert regions of 4q35.2 may have functional significance, possibly also to FSHD, despite their paucity of known genes.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.