Facioscapulohumeral muscular dystrophy (FSHD) is a unique dominant disorder 
involving shortening of an array of tandem 3.3 kb repeats. This copy-number 
polymorphic repeat, D4Z4, is present in arrays at both 4q35 and 10q26, but only 
4q35 arrays with one to 10 copies of the repeat are linked to FSHD. The most 
popular model for how the 4q35 array-shortening causes FSHD is that it results 
in a loss of postulated D4Z4 heterochromatinization, which spreads proximally, 
leading to overexpression of FSHD genes in cis. This would be similar to a loss 
of position-effect variegation (PEV) in Drosophila. To test for the putative 
heterochromatinization, we quantitated chromatin immunoprecipitation with an 
antibody for acetylated histone H4 that discriminates between constitutive 
heterochromatin and unexpressed euchromatin. Contrary to the above model, H4 
acetylation levels of a non-repeated region adjacent to the 4q35 and 10q26 D4Z4 
arrays in normal and FSHD lymphoid cells were like those in unexpressed 
euchromatin and not constitutive heterochromatin. Also, these control and FSHD 
cells displayed similar H4 hyperacetylation (like that of expressed genes) at 
the 5' regions of 4q35 candidate genes FRG1 and ANT1. Contrary to the 
loss-of-PEV model and a recent report, there was no position-dependent increase 
in transcript levels from these genes in FSHD skeletal muscle samples compared 
with controls. Our results favor a new model for the molecular genetic etiology 
of FSHD, such as, differential long-distance cis looping that depends upon the 
presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 
3.3 kb repeat.