Sato Noriko, Kondo Mitsumasa, Arai Ken-ichi
Cytokine Project, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
Biochem Biophys Res Commun. 2006 Jun 9;344(3):845-51. doi: 10.1016/j.bbrc.2006.04.007. Epub 2006 Apr 19.
Somatic DNA methylation patterns are determined in part by the de novo methylation that occurs after early embryonic demethylation. Oct-3/4, a pluripotency gene, is unmethylated in the blastocyst, but undergoes de novo methylation and silencing during gastrulation. Here we show that the transcriptional repressor GCNF recruits DNA methyltransferase to the Oct-3/4 promoter and facilitates its methylation. Although acetylation of histone H3 at lysine 9 (K9) and/or 14 (K14) and methylation of H3 at lysine 4 (K4) decrease during this period, as do Oct-3/4 transcript levels, H3K9 and H3K27 methylation levels remain constant, indicating that DNA methylation does not require repressive histone modifications. We found that GCNF interacts directly with Dnmt3 molecule(s) and verified that this interaction induces the methylation of the Oct-3/4 promoter. Our finding suggests a model in which differentiation-induced GCNF recruits de novo DNA methyltransferase and facilitates the silencing of a pluripotency gene.
体细胞DNA甲基化模式部分由早期胚胎去甲基化后发生的从头甲基化决定。多能性基因Oct-3/4在囊胚中未甲基化，但在原肠胚形成过程中经历从头甲基化并沉默。在这里，我们表明转录抑制因子GCNF将DNA甲基转移酶招募到Oct-3/4启动子并促进其甲基化。尽管在此期间组蛋白H3赖氨酸9（K9）和/或14（K14）的乙酰化以及H3赖氨酸4（K4）的甲基化减少，Oct-3/4转录水平也下降，但H3K9和H3K27甲基化水平保持不变，表明DNA甲基化不需要抑制性组蛋白修饰。我们发现GCNF直接与Dnmt3分子相互作用，并证实这种相互作用诱导Oct-3/4启动子的甲基化。我们的发现提出了一种模型，其中分化诱导的GCNF招募从头DNA甲基转移酶并促进多能性基因的沉默。
