Abstract
Altering cytosine methylation by genetic means leads to a variety of developmental defects in mice1, plants2,3,4,5 and fungi6,7. Deregulation of cytosine methylation also has a role in human carcinogenesis8. In some cases, these defects have been tied to the inheritance of epigenetic alterations (such as chromatin imprints and DNA methylation patterns) that do not involve changes in DNA sequence3,8,9,10. Using a forward genetic screen, we identified a gene (DDM1, decrease in DNA methylation) from the flowering plant Arabidopsis thaliana required to maintain normal cytosine methylation patterns11. Additional ddm1 alleles (som4, 5, 6, 7, 8) were isolated in a selection for mutations that relieved transgene silencing12 (E.J.R., unpublished data). Loss of DDM1 function causes a 70% reduction of genomic cytosine methylation, with most of the immediate hypomethylation occurring in repeated sequences11. In contrast, many low-copy sequences initially retain their methylation in ddm1 homozygotes, but lose methylation over time as the mutants are propagated through multiple generations by self-pollination3,13. The progressive effect of ddm1 mutations on low-copy sequence methylation suggests that ddm1 mutations compromise the efficiency of methylation of newly incorporated cytosines after DNA replication. In parallel with the slow decay of methylation during inbreeding, ddm1 mutants accumulate heritable alterations (mutations or stable epialleles) at dispersed sites in the genome that lead to morphological abnormalities3,5,14. Here we report that DDM1 encodes a SWI2/SNF2-like protein, implicating chromatin remodelling as an important process for maintenance of DNA methylation and genome integrity.
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References
Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Finnegan, E.J., Peacock, W.J. & Dennis, E.S. Reduced DNA methylation in Arabidopsis thaliana results in abnormal plant development. Proc. Natl Acad. Sci. USA 93, 8449–8454 ( 1996).
Kakutani, T., Jeddeloh, J.A., Flowers, S.K., Munakata, K. & Richards, E.J. Developmental abnormalities and epimutations associated with DNA hypomethylation mutations. Proc. Natl Acad. Sci. USA 93, 12406–12411 (1996).
Ronemus, M.J., Galbiati, M., Ticknor, C., Chen, J. & Dellaporta, S.L. Demethylation-induced developmental pleiotropy in Arabidopsis. Science 273, 654–657 (1996).
Kakutani, T. Genetic characterization of late-flowering traits induced by DNA hypomethylation mutation in Arabidopsis thaliana. Plant J. 12 , 1447–1451 (1998).
Foss, H.M., Roberts, C.J., Claeys, K.M. & Selker, E.U. Abnormal chromosome behavior in Neurospora mutants defective in DNA methylation. Science 262, 1737– 1741 (1993).
Malagnac, F. et al. A gene essential for de novo methylation and development in Ascobolus reveals a novel type of eukaryotic DNA methyltransferase structure. Cell 91, 281– 290 (1997).
Baylin, S.B., Herman, J.G., Graff, J.R., Vertino, P.M. & Issa, J.-P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141–196 (1998).
Jacobsen, S.E. & Meyerowitz, E.M. Hypermethylated SUPERMAN epigenetic alleles in Arabidopsis. Science 277, 1100–1103 (1997).
Martienssen, R. Chromosomal imprinting in plants. Curr. Opin. Genet. Dev. 8, 240–244 (1998).
Vongs, A., Kakutani, T., Martienssen, R.A. & Richards, E.J. Arabidopsis thaliana DNA methylation mutants. Science 260, 1926–1928 (1993).
Mittelsten Scheid, O., Afsar, K. & Paszkowski, J. Release of epigenetic gene silencing by trans-acting mutations in Arabidopsis. Proc. Natl Acad. Sci. USA 95, 632–637 (1998).
Jeddeloh, J.A., Bender, J. & Richards, E.J. The DNA methylation locus DDM1 is required for maintenance of gene silencing in Arabidopsis. Genes Dev. 12, 1714–1725 ( 1998).
Richards, E.J. DNA methylation and plant development. Trends Genet. 13, 319–323 (1997).
Kakutani, T., Jeddeloh, J.A. & Richards, E.J. Characterization of an Arabidopsis thaliana DNA hypomethylation mutant. Nucleic Acids Res. 23, 130–137 (1995).
Pazin, M.J. & Kadonaga, J.T. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions? Cell 88, 737–740 (1997).
Cairns, B.R. Chromatin remodeling machines: similar motors, ulterior motives. Trends Biochem. Sci. 23, 20–25 (1998).
Aihara, T. et al. Cloning and mapping of SMARCA5 encoding hSNF2H, a novel human homologue of Drosophila ISWI. Cytogenet. Cell Genet. 81, 191–193 (1998).
Jarvis, C.D. et al. A novel putative helicase produced in early murine lymphocytes. Gene 169, 203–207 (1996).
Bork, P. & Koonin, E.V. An expanding family of helicases within the 'DEAD/H' superfamily. Nucleic Acids Res. 21, 751–752 (1993).
Eisen, J.A., Swider, K.S. & Hanawalt, P.C. Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Res. 23, 2715–2723 (1995).
LeRoy, G., Orphanides, G., Lane, W.S. & Reinberg, D. Requirement of RSF and FACT for transcription of chromatin templates in vitro. Science 282, 1900– 1904 (1998).
Eden, S., Hashimshony, T., Keshet, I., Cedar, H. & Thorne, A.W. DNA methylation models histone acetylation. Nature 394, 842 ( 1998).
Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187– 191 (1998).
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Selker, E.U. Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc. Natl Acad. Sci. USA 95, 9430– 9435 (1998).
Wade, P.A., Jones, P.L., Vermaak, D. & Wolffe, A.P. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8, 843–846 (1998).
Zhang, Y., LeRoy, G., Seelig, H.-P., Lane, W.S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).
Konieczny, A. & Ausubel, F.M. A procedure for mapping Arabidopsis mutations using co-dominant ecotype-specific PCR-based markers. Plant J. 4, 403–410 ( 1993).
Choi, S., Creelman, R.A., Mullet, J.E. & Wing, R.A. Construction and characterization of a bacterial artificial chromosome library of Arabidopsis thaliana. Weeds World 2, 17–20 (1995).
Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).
Acknowledgements
We thank H. Adler, J. Bender, C. Dean, D. Della-Penna, K. Dewar, J. Ecker, H. Goodman, T. Ho, L. Medrano, E. Meyerowitz, B. Osborne, G. Picard, C. Rock, R. Schmidt, M. Stammers, J. Zeevaart and the Arabidopsis Biological Resource Center at The Ohio State University for markers, materials and information that facilitated the chromosome walk to DDM1; S.K. Flowers, T. Kakutani and C. Keane for initial genetic mapping data; C. Pikaard for critical reading of the manuscript; J. Eisen for expertise and input on SNF2 molecular phylogeny; W. Barnes, J. Dover and M. Johnston for help with DNA sequencing; H.-f. Kuo for determining the sequence of ddm1-6 and ddm1-7; and O. Mittelsten Scheid and J. Paszkowski for providing the som mutant material. This work was supported by a grant from the National Science Foundation (to E.J.R.; MCB 9604972). J.A.J. and T.L.S. were supported by a Predoctoral Fellowship from the Monsanto Company and an NSF training grant (BIR 9256779).
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Jeddeloh, J., Stokes, T. & Richards, E. Maintenance of genomic methylation requires a SWI2/SNF2-like protein . Nat Genet 22, 94–97 (1999). https://doi.org/10.1038/8803
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DOI: https://doi.org/10.1038/8803
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