Wang Jing, Hevi Sarah, Kurash Julia K, Lei Hong, Gay Frédérique, Bajko Jeffrey, Su Hui, Sun Weitao, Chang Hua, Xu Guoliang, Gaudet François, Li En, Chen Taiping
Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Nat Genet. 2009 Jan;41(1):125-9. doi: 10.1038/ng.268. Epub 2008 Dec 21.
Histone methylation and DNA methylation cooperatively regulate chromatin structure and gene activity. How these two systems coordinate with each other remains unclear. Here we study the biological function of lysine-specific demethylase 1 (LSD1, also known as KDM1 and AOF2), which has been shown to demethylate histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9). We show that LSD1 is required for gastrulation during mouse embryogenesis. Notably, targeted deletion of the gene encoding LSD1 (namely, Aof2) in embryonic stem (ES) cells induces progressive loss of DNA methylation. This loss correlates with a decrease in DNA methyltransferase 1 (Dnmt1) protein, as a result of reduced Dnmt1 stability. Dnmt1 protein is methylated in vivo, and its methylation is enhanced in the absence of LSD1. Furthermore, Dnmt1 can be methylated by Set7/9 (also known as KMT7) and demethylated by LSD1 in vitro. Our findings suggest that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.
组蛋白甲基化和DNA甲基化共同调节染色质结构和基因活性。这两个系统如何相互协调仍不清楚。在此，我们研究了赖氨酸特异性去甲基化酶1（LSD1，也称为KDM1和AOF2）的生物学功能，该酶已被证明可使组蛋白H3的赖氨酸4（H3K4）和赖氨酸9（H3K9）去甲基化。我们发现LSD1是小鼠胚胎发育过程中原肠胚形成所必需的。值得注意的是，在胚胎干细胞（ES细胞）中靶向缺失编码LSD1的基因（即Aof2）会导致DNA甲基化的逐渐丧失。这种丧失与DNA甲基转移酶1（Dnmt1）蛋白的减少相关，这是由于Dnmt1稳定性降低所致。Dnmt1蛋白在体内发生甲基化，并且在缺乏LSD1的情况下其甲基化增强。此外，Dnmt1在体外可被Set7/9（也称为KMT7）甲基化并被LSD1去甲基化。我们的研究结果表明，LSD1使Dnmt1去甲基化并使其稳定，从而在组蛋白和DNA甲基化系统之间提供了一个先前未知的机制联系。
