Xi Sichuan, Zhu Heming, Xu Hong, Schmidtmann Anja, Geiman Theresa M, Muegge Kathrin
Laboratory of Cancer Prevention, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702-1201, USA.
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14366-71. doi: 10.1073/pnas.0703669104. Epub 2007 Aug 28.
Polycomb-mediated repression and DNA methylation are important epigenetic mechanisms of gene silencing. Recent evidence suggests a functional link between the polycomb repressive complex (PRC) and Dnmts in cancer cells. Here we provide evidence that Lsh, a regulator of DNA methylation, is also involved in normal control of PRC-mediated silencing during embryogenesis. We demonstrate that Lsh, a SNF2 homolog, can associate with some Hox genes and regulates Dnmt3b binding, DNA methylation, and silencing of Hox genes during development. Moreover, Lsh can associate with PRC1 components and influence PRC-mediated histone modifications. Thus Lsh is part of a physiological feedback loop that reinforces DNA methylation and silencing of PRC targets.
多梳蛋白介导的基因沉默和DNA甲基化是重要的表观遗传机制。最近的证据表明癌细胞中多梳抑制复合物(PRC)与DNA甲基转移酶(Dnmts)之间存在功能联系。在此,我们提供证据表明,作为DNA甲基化调节因子的Lsh,在胚胎发育过程中也参与PRC介导的基因沉默的正常调控。我们证明,作为SNF2同源物的Lsh,可与一些Hox基因结合,并在发育过程中调节Dnmt3b的结合、DNA甲基化以及Hox基因的沉默。此外,Lsh可与PRC1组分结合,并影响PRC介导的组蛋白修饰。因此,Lsh是强化PRC靶标的DNA甲基化和基因沉默的生理反馈回路的一部分。