Gilbert Nick, Thomson Inga, Boyle Shelagh, Allan James, Ramsahoye Bernard, Bickmore Wendy A
Medical Research Council Human Genetics Unit, Edinburgh, Scotland, UK.
J Cell Biol. 2007 May 7;177(3):401-11. doi: 10.1083/jcb.200607133.
DNA methylation has been implicated in chromatin condensation and nuclear organization, especially at sites of constitutive heterochromatin. How this is mediated has not been clear. In this study, using mutant mouse embryonic stem cells completely lacking in DNA methylation, we show that DNA methylation affects nuclear organization and nucleosome structure but not chromatin compaction. In the absence of DNA methylation, there is increased nuclear clustering of pericentric heterochromatin and extensive changes in primary chromatin structure. Global levels of histone H3 methylation and acetylation are altered, and there is a decrease in the mobility of linker histones. However, the compaction of both bulk chromatin and heterochromatin, as assayed by nuclease digestion and sucrose gradient sedimentation, is unaltered by the loss of DNA methylation. This study shows how the complete loss of a major epigenetic mark can have an impact on unexpected levels of chromatin structure and nuclear organization and provides evidence for a novel link between DNA methylation and linker histones in the regulation of chromatin structure.
DNA甲基化与染色质浓缩及核组织有关，尤其是在组成型异染色质位点。其介导方式尚不清楚。在本研究中，我们使用完全缺乏DNA甲基化的突变小鼠胚胎干细胞，表明DNA甲基化影响核组织和核小体结构，但不影响染色质压实。在没有DNA甲基化的情况下，着丝粒周围异染色质的核聚集增加，并且初级染色质结构发生广泛变化。组蛋白H3甲基化和乙酰化的整体水平发生改变，并且连接组蛋白的流动性降低。然而，通过核酸酶消化和蔗糖梯度沉降分析，大量染色质和异染色质的压实并未因DNA甲基化的缺失而改变。这项研究表明，主要表观遗传标记的完全缺失如何对染色质结构和核组织的意外水平产生影响，并为DNA甲基化与连接组蛋白在染色质结构调节中的新联系提供了证据。
