DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing

Alexander Saveliev, Christopher Everett, Tammy Sharpe, Zoë Webster and Richard Festenstein ()
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Alexander Saveliev: Imperial College School of Medicine, Hammersmith Campus
Christopher Everett: Imperial College School of Medicine, Hammersmith Campus
Tammy Sharpe: Imperial College School of Medicine, Hammersmith Campus
Zoë Webster: MRC Clinical Sciences Centre, Hammersmith Campus
Richard Festenstein: Imperial College School of Medicine, Hammersmith Campus

Nature, 2003, vol. 422, issue 6934, 909-913

Abstract: Abstract Gene repression is crucial to the maintenance of differentiated cell types in multicellular organisms, whereas aberrant silencing can lead to disease. The organization of DNA into chromatin and heterochromatin1 is implicated in gene silencing. In chromatin, DNA wraps around histones, creating nucleosomes. Further condensation of chromatin, associated with large blocks of repetitive DNA sequences, is known as heterochromatin. Position effect variegation (PEV) occurs when a gene is located abnormally close to heterochromatin, silencing the affected gene in a proportion of cells1. Here we show that the relatively short triplet-repeat expansions found in myotonic dystrophy and Friedreich's ataxia confer variegation of expression on a linked transgene in mice. Silencing was correlated with a decrease in promoter accessibility and was enhanced by the classical PEV modifier heterochromatin protein 1 (HP1). Notably, triplet-repeat-associated variegation was not restricted to classical heterochromatic regions but occurred irrespective of chromosomal location. Because the phenomenon described here shares important features with PEV, the mechanisms underlying heterochromatin-mediated silencing might have a role in gene regulation at many sites throughout the mammalian genome and modulate the extent of gene silencing and hence severity in several triplet-repeat diseases.

Date: 2003
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DOI: 10.1038/nature01596

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