Effect of ageing on reactivation of the human X-linked HPRT locus.
In mammals, X-chromosome dosage compensation is achieved by inactivating one X chromosome in female cells. To test the hypothesis that genes on the silent X chromosome reactivate as a consequence of ageing, we examined the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 41 women who are heterozygous for mutations at this locus, leading to severe deficiency of the enzyme (Lesch-Nyhan syndrome). We find that heterozygotes who are more than 10 yr old have an excess of HPRT+ skin fibroblast clones (59% rather than the 50% expected as a consequence of random X inactivation) but this excess does not increase with age. Further studies of eight of these heterozygotes show that the silent locus does not detectably reactivate spontaneously in culture, but only in response to treatment with 5-aza-2-deoxycytidine, a potent inhibitor of methylation. There is no age difference in the frequency of this reactivation as assayed by HATr clones, and a more sensitive autoradiographic assay shows only a twofold difference between young and old heterozygotes. Thus, age-related reactivation is not a feature of all X-linked loci, and may have species, tissue and locus-specific determinants.
Migeon
B R
BR
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Axelman
J
J
Beggs
A H
AH
D000375:Aging; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077209:Decitabine; D004303:Dosage Compensation, Genetic; D005260:Female; D006579:Heterozygote; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000235:genetics; D012867:Skin / Q000201:enzymology; D014960:X Chromosome
D000077209:Decitabine; D007041:Hypoxanthine Phosphoribosyltransferase; D001374:Azacitidine