Maintenance of genomic methylation requires a SW12/SNF2-like protein
Maintenance of genomic methylation requires a SW12/SNF2-like protein
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DOI：
10.1038/8803
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发表时间：
1999-05-01
期刊：
影响因子：
30.8
通讯作者：
Richards, EJ
中科院分区：
文献类型：
--
作者：
Jeddeloh, JA;Stokes, TL;Richards, EJ
通过遗传途径改变胞嘧啶甲基化会导致小鼠(1)、植物（2-5）和真菌（6,7）的各种发育缺陷。胞嘧啶甲基化的失调也在人类致癌过程中发挥作用(8)。在某些情况下，这些缺陷与不涉及DNA序列变化的表观遗传改变（如染色质印记和DNA甲基化模式）有关（3,8-10）。通过前向遗传筛选，我们从开花植物拟南芥中发现了一个维持正常胞嘧啶甲基化模式所需的基因（DDM1， DNA甲基化减少）（11）。另外的ddm1等位基因（som4、5、6、7、8）在缓解转基因沉默的突变选择中被分离出来（12）（e.j.r.，未发表的数据）。DDM1功能的丧失导致基因组胞嘧啶甲基化减少70%，大多数直接低甲基化发生在重复序列中（11）。相比之下，许多低拷贝序列最初在ddm1纯合子中保留其甲基化，但随着时间的推移，随着突变体通过自花授粉在多代繁殖而失去甲基化（3,13）。ddm1突变对低拷贝序列甲基化的进行性影响表明，ddm1突变损害了DNA复制后新合并的胞嘧啶的甲基化效率。与近交过程中甲基化的缓慢衰减同时，ddm1突变体在基因组的分散位点积累可遗传的改变（突变或稳定的外显子），从而导致形态异常（3,5,14）。在这里，我们报道了DDM1编码SWI2/ snf2样蛋白，暗示染色质重塑是维持DNA甲基化和基因组完整性的重要过程。
Altering cytosine methylation by genetic means leads to a variety of developmental defects in mice(1), plants(2-5) and fungi(6,7) Deregulation of cytosine methylation also has a role in human carcinogenesis(8). 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(3,8-10). 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 patterns(11). Additional ddm1 alleles (som4, 5, 6, 7, 8) were isolated in a selection for mutations that relieved transgene silencing(12) (E.J.R., unpublished data).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(11). 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(3,13). 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 abnormalities(3,5,14). 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.