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Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation

Nature Genetics volume 24, pages 368371 (2000) | Download Citation

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Abstract

A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases1,2. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and α-thalassaemia1. This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes3. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

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References

  1. 1.

    , , & Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome). Cell 80, 837–845 (1995).

  2. 2.

    et al. Mutations in a transcriptional regulator (hATRX) establish the functional significance of a PHD-like domain. Nature Genet. 17, 146–148 (1997).

  3. 3.

    et al. Localisation of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes. Proc. Natl Acad. Sci. USA 96, 13983–13988 (1999).

  4. 4.

    , , & Immunostaining of nucleolus organizers in mammalian cells by a human autoantibody against the polymerase I transcription factor UBF. Cell. Mol. Biol. 38, 841–851 (1992).

  5. 5.

    , & The ability of the restriction endonuclease EcoRI to digest hemi-methylated versus fully cytosine-methylated DNA of the herpes tk promoter region. Gene 74, 147–149 (1988).

  6. 6.

    , & Characterisation of a human Y chromosome repeated sequence and related sequences in higher primates. Chromosoma 87, 491–502 (1982).

  7. 7.

    , & Human satellite I sequences include a male specific 2.47 kb tandemly repeated unit containing one Alu family member per repeat. Nucleic Acids Res. 12, 2887–2900 (1984).

  8. 8.

    et al. Structure and polymorphism of human telomere-associated DNA. Cell 63, 119–132 (1990).

  9. 9.

    , & Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nature Genet. 22, 94–97 (1999).

  10. 10.

    , , & Arabidopsis thaliana DNA methylation mutants. Science 260, 1926–1928 (1993).

  11. 11.

    , & Characterization of an Arabidopsis thaliana DNA hypomethylation mutant. Nucleic Acids Res. 23, 130–137 (1995).

  12. 12.

    Gene silencing: maintaining methylation patterns. Curr. Biol. 9, R617–R619 (1999).

  13. 13.

    et al. Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 236, 87–95 (1999).

  14. 14.

    , , & DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

  15. 15.

    et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–190 (1999).

  16. 16.

    et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).

  17. 17.

    et al. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23, 62–66 (1999).

  18. 18.

    et al. The relationship between chromosome structure and function at a human telomeric region. Nature Genet. 15, 252–257 (1997).

  19. 19.

    & Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres. Hum. Mol. Genet. 4, 2189–2197 (1995).

  20. 20.

    , , & Meiotically and mitotically stable inheritance of DNA hypomethylation induced by ddm1 mutation of Arabidopsis thaliana. Genetics 151, 831–838 (1999).

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Acknowledgements

We thank W.R.A. Brown and D. Jackson for probes; M. Valdivia for anti-UBF antibodies; V.J. Buckle for helpful advice; D. Jackson for probes to detect the human ribosomal DNA arrays; T. Jones and I. Smith for help with the analysis of methylcytosine levels using HPLC; and D.J. Weatherall for support and encouragement. The work was supported by the MRC, the Wellcome Trust (R.J.G.), Action Research (D.M.O.) and the C.J. Marin Travelling Fellowship (D.G.).

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Affiliations

  1. MRC Molecular Haematology Unit, Institute of Molecular Medicine, Oxford, UK.

    • Tarra L. McDowell
    • , Delia M. O'Rourke
    • , David Garrick
    • , Helena Ayyub
    •  & Douglas R. Higgs
  2. Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.

    • Richard J. Gibbons
    •  & Sundhya Raman

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Correspondence to Douglas R. Higgs.

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DOI

https://doi.org/10.1038/74191

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