Methylation of the Hypoxanthine Phosphoribosyltransferase Locus on the Human X Chromosome: Implications for X-Chromosome Inactivation

• Published in: Proceedings of the National Academy of Sciences - PNAS 1984-05, Vol.81 (9), p.2806-2810
• Main Authors: Wolf, Stanley F., Jolly, Douglas J., Lunnen, Keith D., Friedmann, Theodore, Migeon, Barbara R.
• Format: Article
• Language: English
• Subjects: Alleles; Base Sequence; DNA; Dosage Compensation, Genetic; Female; Fibroblasts; Gene Expression Regulation; Genes; Genetic loci; Human X chromosome; Humans; Hybridity; Hypoxanthine Phosphoribosyltransferase - genetics; Male; Methylation; Sex chromosomes; Sex Factors; X chromosome; X Chromosome - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.81.9.2806

To explore the role of DNA methylation in maintaining dosage compensation of X chromosome-linked genes and in regulating the transcriptional activity of ``housekeeping'' genes, we characterized DNA methylation of active, inactive, and derepressed alleles at the locus for hypoxanthine phosphoribosyltransferase (HPRT) on the human X chromosome. The methylation of Hpa II and Hha I sites in HPRT alleles on the active X chromosome was the same in all tissues. The consensus pattern includes hypomethylation of 5′clustered sites and extensive methylation of the 3′sequence. The striking feature of methylation of inactive X-chromosome alleles is nonuniformity and less extensive hypomethylation of the 5′cluster. Analysis of HPRT alleles reactivated in response to 5-azacytidine showed at least partial restoration of the consensus pattern. These observations indicate that methylation of housekeeping genes on the X chromosome is the same as that of autosomal ones and that the overall pattern and methylation of multiple sites within a cluster may cooperate to facilitate transcription. Furthermore, the fidelity of methylation of the active allele and the extensive drift in methylation of the inactive allele suggest that mechanisms involved in X-chromosome dosage compensation may be directed at the active rather than inactive X chromosome.