• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Sep 1987; 84(17): 6210–6214.
PMCID: PMC299040

DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation.

Abstract

In marsupials and eutherian mammals, X chromosome dosage compensation is achieved by inactivating one X chromosome in female cells; however, in marsupials, the inactive X chromosomes is always paternal, and some genes on the chromosome are partially expressed. To define the role of DNA methylation in maintenance of X chromosome inactivity, we examined loci for glucose-6-phosphate dehydrogenase and hypoxanthine phosphoribosyltransferase in a North American marsupial, the opossum Didelphis virginiana, by using genomic hybridization probes cloned from this species. We find that these marsupial genes are like their eutherian counterparts, with respect to sex differences in methylation of nuclease-insensitive (nonregulatory) chromatin. However, with respect to methylation of the nuclease-hypersensitive (regulatory) chromatin of the glucose-6-phosphate dehydrogenase locus, the opossum gene differs from those of eutherians, as the 5' cluster of CpG dinucleotides is hypomethylated in the paternal as well as the maternal gene. Despite hypomethylation of the 5' CpG cluster, the paternal allele, identified by an enzyme variant, is at best partially expressed; therefore, factors other than methylation are responsible for repression. In light of these results, it seems that the role of DNA methylation in eutherian X dosage compensation is to "lock in" the process initiated by such factors. Because of similarities between dosage compensation in marsupials and trophectoderm derivatives of eutherians, we propose that differences in timing of developmental events--rather than differences in the basic mechanisms of X inactivation--account for features of dosage compensation that differ among mammals.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lyon MF. X-chromosome inactivation and developmental patterns in mammals. Biol Rev Camb Philos Soc. 1972 Jan;47(1):1–35. [PubMed]
  • Migeon BR. Stability of X chromosomal inactivation in human somatic cells. Nature. 1972 Sep 8;239(5367):87–89. [PubMed]
  • Johnston PG, Sharman GB. Studies on metatherian sex chromosomes. I. Inheritance and inactivation of sex-linked allelic genes determining glucose-6-phosphate dehydrogenase variation in kangaroos. Aust J Biol Sci. 1975 Dec;28(5-6):567–574. [PubMed]
  • Richardson BJ, Czuppon AB, Sharman GB. Inheritance of glucose-6-phosphate dehydrogenase variation in kangaroos. Nat New Biol. 1971 Mar 31;230(13):154–155. [PubMed]
  • Cooper DW, VandeBerg JL, Sharman GB, Poole WE. Phosphoglycerate kinase polymorphism in kangaroos provides further evidence for paternal X inactivation. Nat New Biol. 1971 Mar 31;230(13):155–157. [PubMed]
  • VandeBerg JL, Cooper DW, Sharman GB, Poole WE. Studies on metatherian sex chromosomes. IV. X linkage of PGK-A with paternal X inactivation confirmed in erythrocytes of grey kangaroos by pedigree analysis. Aust J Biol Sci. 1977 Apr;30(1-2):115–125. [PubMed]
  • VandeBerg JL, Johnston PG, Cooper DW, Robinson ES. X-chromosome inactivation and evolution in marsupials and other mammals. Isozymes Curr Top Biol Med Res. 1983;9:201–218. [PubMed]
  • Samollow PB, Ford AL, VandeBerg JL. X-linked gene expression in the Virginia opossum: differences between the paternally derived Gpd and Pgk-A loci. Genetics. 1987 Jan;115(1):185–195. [PMC free article] [PubMed]
  • Takagi N. Differentiation of X chromosomes in early female mouse embryos. Exp Cell Res. 1974 May;86(1):127–135. [PubMed]
  • West JD, Frels WI, Chapman VM, Papaioannou VE. Preferential expression of the maternally derived X chromosome in the mouse yolk sac. Cell. 1977 Dec;12(4):873–882. [PubMed]
  • Migeon BR, Do TT. In search of non-random X inactivation: studies of fetal membranes heterozygous for glucose-6-phosphate dehydrogenase. Am J Hum Genet. 1979 Sep;31(5):581–585. [PMC free article] [PubMed]
  • Migeon BR, Wolf SF, Axelman J, Kaslow DC, Schmidt M. Incomplete X chromosome dosage compensation in chorionic villi of human placenta. Proc Natl Acad Sci U S A. 1985 May;82(10):3390–3394. [PMC free article] [PubMed]
  • Migeon BR, Schmidt M, Axelman J, Cullen CR. Complete reactivation of X chromosomes from human chorionic villi with a switch to early DNA replication. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2182–2186. [PMC free article] [PubMed]
  • Liskay RM, Evans RJ. Inactive X chromosome DNA does not function in DNA-mediated cell transformation for the hypoxanthine phosphoribosyltransferase gene. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4895–4898. [PMC free article] [PubMed]
  • Mohandas T, Sparkes RS, Shapiro LJ. Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science. 1981 Jan 23;211(4480):393–396. [PubMed]
  • Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. [PubMed]
  • Melton DW, Konecki DS, Brennand J, Caskey CT. Structure, expression, and mutation of the hypoxanthine phosphoribosyltransferase gene. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2147–2151. [PMC free article] [PubMed]
  • Wolf SF, Jolly DJ, Lunnen KD, Friedmann T, Migeon BR. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc Natl Acad Sci U S A. 1984 May;81(9):2806–2810. [PMC free article] [PubMed]
  • Martini G, Toniolo D, Vulliamy T, Luzzatto L, Dono R, Viglietto G, Paonessa G, D'Urso M, Persico MG. Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J. 1986 Aug;5(8):1849–1855. [PMC free article] [PubMed]
  • Yen PH, Patel P, Chinault AC, Mohandas T, Shapiro LJ. Differential methylation of hypoxanthine phosphoribosyltransferase genes on active and inactive human X chromosomes. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1759–1763. [PMC free article] [PubMed]
  • Lock LF, Melton DW, Caskey CT, Martin GR. Methylation of the mouse hprt gene differs on the active and inactive X chromosomes. Mol Cell Biol. 1986 Mar;6(3):914–924. [PMC free article] [PubMed]
  • Keith DH, Singer-Sam J, Riggs AD. Active X chromosome DNA is unmethylated at eight CCGG sites clustered in a guanine-plus-cytosine-rich island at the 5' end of the gene for phosphoglycerate kinase. Mol Cell Biol. 1986 Nov;6(11):4122–4125. [PMC free article] [PubMed]
  • Wolf SF, Dintzis S, Toniolo D, Persico G, Lunnen KD, Axelman J, Migeon BR. Complete concordance between glucose-6-phosphate dehydrogenase activity and hypomethylation of 3' CpG clusters: implications for X chromosome dosage compensation. Nucleic Acids Res. 1984 Dec 21;12(24):9333–9348. [PMC free article] [PubMed]
  • Toniolo D, D'Urso M, Martini G, Persico M, Tufano V, Battistuzzi G, Luzzatto L. Specific methylation pattern at the 3' end of the human housekeeping gene for glucose 6-phosphate dehydrogenase. EMBO J. 1984 Sep;3(9):1987–1995. [PMC free article] [PubMed]
  • Wolf SF, Migeon BR. Clusters of CpG dinucleotides implicated by nuclease hypersensitivity as control elements of housekeeping genes. Nature. 1985 Apr 4;314(6010):467–469. [PubMed]
  • Wolf SF, Mareni CE, Migeon BR. Isolation and characterization of cloned DNA sequences that hybridize to the human X chromosome. Cell. 1980 Aug;21(1):95–102. [PubMed]
  • Cooper DN, Taggart MH, Bird AP. Unmethylated domains in vertebrate DNA. Nucleic Acids Res. 1983 Feb 11;11(3):647–658. [PMC free article] [PubMed]
  • Beggs AH, Axelman J, Migeon BR. Reactivation of X-linked genes in human fibroblasts transformed by origin-defective SV40. Somat Cell Mol Genet. 1986 Nov;12(6):585–594. [PubMed]
  • Cullen CR, Hubberman P, Kaslow DC, Migeon BR. Comparison of factor IX methylation on human active and inactive X chromosomes: implications for X inactivation and transcription of tissue-specific genes. EMBO J. 1986 Sep;5(9):2223–2229. [PMC free article] [PubMed]
  • Kratzer PG, Chapman VM, Lambert H, Evans RE, Liskay RM. Differences in the DNA of the inactive X chromosomes of fetal and extraembryonic tissues of mice. Cell. 1983 May;33(1):37–42. [PubMed]
  • Krumlauf R, Chapman VM, Hammer RE, Brinster R, Tilghman SM. Differential expression of alpha-fetoprotein genes on the inactive X chromosome in extraembryonic and somatic tissues of a transgenic mouse line. Nature. 1986 Jan 16;319(6050):224–226. [PubMed]
  • Gartler SM, Riggs AD. Mammalian X-chromosome inactivation. Annu Rev Genet. 1983;17:155–190. [PubMed]
  • Kratzer PG, Chapman VM. X chromosome reactivation in oocytes of Mus caroli. Proc Natl Acad Sci U S A. 1981 May;78(5):3093–3097. [PMC free article] [PubMed]
  • Monk M, Harper MI. Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos. Nature. 1979 Sep 27;281(5729):311–313. [PubMed]
  • Kratzer PG, Gartler SM. HGPRT activity changes in preimplantation mouse embryos. Nature. 1978 Aug 3;274(5670):503–504. [PubMed]
  • Lock LF, Takagi N, Martin GR. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell. 1987 Jan 16;48(1):39–46. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links