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Human Molecular Genetics Advance Access originally published online on September 23, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 22 2909-2921
DOI: 10.1093/hmg/ddg323
© 2003 Oxford University Press

Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q

Guanchao Jiang1, Fan Yang1, Petra G. M. van Overveld2, Vettaikorumakankav Vedanarayanan3, Silvere van der Maarel2 and Melanie Ehrlich1,*

1Human Genetics Program and Department of Biochemistry, Tulane Medical School, New Orleans, LA 70112, USA, 2Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands and 3Department of Neurology, University of Mississippi Medical School, Jackson, MS, 39216, USA

Received July 23, 2003; Revised September 3, 2003; Accepted September 15, 2003

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.

* To whom correspondence should be addressed. Tel: +1 5045842449; Fax: +1 5045841763; Email: ehrlich{at}tulane.edu


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