Wolf S F, Jolly D J, Lunnen K D, Friedmann T, Migeon B R
Proc Natl Acad Sci U S A. 1984 May;81(9):2806-10. 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.
为了探究DNA甲基化在维持X染色体连锁基因的剂量补偿以及调节“管家”基因转录活性中的作用，我们对人类X染色体上次黄嘌呤磷酸核糖转移酶（HPRT）基因座的活性、非活性和去抑制等位基因的DNA甲基化进行了表征。活性X染色体上HPRT等位基因中Hpa II和Hha I位点的甲基化在所有组织中都是相同的。一致模式包括5' 簇状位点的低甲基化和3' 序列的广泛甲基化。非活性X染色体等位基因甲基化的显著特征是5' 簇的不均匀性和较少的低甲基化。对响应5-氮杂胞苷重新激活的HPRT等位基因的分析表明，一致模式至少部分得以恢复。这些观察结果表明，X染色体上管家基因的甲基化与常染色体上的相同，并且簇内多个位点的总体模式和甲基化可能协同促进转录。此外，活性等位基因甲基化的保真度以及非活性等位基因甲基化的广泛漂移表明，参与X染色体剂量补偿的机制可能针对活性而非非活性X染色体。
