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

Abstract

Altering cytosine methylation by genetic means leads to a variety of developmental defects in mice, plants and fungi. Deregulation of cytosine methylation also has a role in human carcinogenesis. 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 sequence. 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 patterns. Additional ddm1 alleles (som4, 5, 6, 7, 8) were isolated in a selection for mutations that relieved transgene silencing (E.J.R., unpublished data).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 sequences. 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-pollination. 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 abnormalities. 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.

DNA methylation, methyltransferases, and cancer

“…For example, mutations in ATP-dependent chromatin remodeling factors like ATRX in mammals and DDM1 in arabidopsis have revealed subtle to profound defects, respectively, in DNA methylation patterns (Gibbons et al, 2000;Jeddeloh et al, 1999). The closest mammalian homolog to DDM1, termed Lsh (lymphoid speci®c helicase), has recently been disrupted in mice (Geiman and Muegge, 2000) and it will be of great interest to learn the e ects of this mutation on global methylation patterns.…”

Repeat elements and the Arabidopsis DNA methylation landscape

“…Furthermore, CHH methylation is not completely abolished in drm1drm2cmt3 triple mutants (Cokus et al, 2008;Lister et al, 2008). This and other observations suggest that some CHH methylation is in fact laid down by MET1 or additional DNA MTases, presumably in an RNAi-independent manner ( In addition to the factors listed above, the ATPase SWI2/SNF2 chromatin remodeler DECREASE IN DNA METHYLATION 1 (DDM1) has an essential role in the maintenance of high DNA methylation levels over repeat elements (Vongs et al, 1993;Jeddeloh et al, 1999;Lippman et al, 2004;Teixeira et al, 2009). Although the mechanism of action of DDM1 remains mysterious, studies carried out on the mammalian homolog lymphoid-specific helicase (LSH) suggest that it may serve as a recruiting factor for DNA MTases and histone deacetylases at target loci (Myant and Stancheva, 2008).…”

Chromatin remodeling by ATP‐dependent molecular machines

“…(61) Also, the plant DDM1 protein is a chromatinremodeling factor that is important for the maintenance of DNA methylation and genome stability. (62,63) In the future, it will be interesting to determine whether Rad54, ARIP4, CSB and DDM1 naturally exist in multisubunit complexes.…”