DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing.
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 heterochromatin 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 cells. 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.
Saveliev
Alexander
A
CSC Gene Control Mechanisms and Disease Group, Experimental Genetics, Faculty of Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Everett
Christopher
C
Sharpe
Tammy
T
Webster
Zoë
Z
Festenstein
Richard
R
D000818:Animals; D001483:Base Sequence; D018801:CD2 Antigens / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005434:Flow Cytometry; D005621:Friedreich Ataxia / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009223:Myotonic Dystrophy / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics / Q000502:physiology; D018911:Trinucleotide Repeats / Q000235:genetics / Q000502:physiology*
D018801:CD2 Antigens; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D000090266:Chromobox Protein Homolog 5