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Maintenance of genomic methylation requires a SWI2/SNF2-like protein

Nature Genetics volume 22, pages 94–97 (1999)Cite this article

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ddm1 alleles (som4, 5, 6, 7, 8) were isolated in a selection for mutations that relieved transgene silencing12 (E.J.R., unpublished data).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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Figure 1: Map-based isolation of A. thaliana DDM1.
Figure 2: DDM1 structure and identification.
Figure 3: A. thaliana DDM1 encodes a SWI2/SNF2-like protein.

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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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  1. Jeffrey A. Jeddeloh

    Present address: Bacteriology Division, US Army Medical Research Institute of Infectious Disease, 1425 Porter Street, Frederick, Maryland, 21702-5011, USA

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  1. Department of Biology, Washington University, One Brookings Drive, St. Louis, 63130, Missouri, USA

    Jeffrey A. Jeddeloh, Trevor L. Stokes & Eric J. Richards

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Correspondence to Eric J. Richards.

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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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