Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Cell Rep. 2013 Feb 21;3(2):291-300. doi: 10.1016/j.celrep.2013.01.011. Epub 2013 Feb 9.
DNA methylation in mammals is highly dynamic during germ cell and preimplantation development but is relatively static during the development of somatic tissues. 5-hydroxymethylcytosine (5hmC), created by oxidation of 5-methylcytosine (5mC) by Tet proteins and most abundant in the brain, is thought to be an intermediary toward 5mC demethylation. We investigated patterns of 5mC and 5hmC during neurogenesis in the embryonic mouse brain. 5hmC levels increase during neuronal differentiation. In neuronal cells, 5hmC is not enriched at enhancers but associates preferentially with gene bodies of activated neuronal function-related genes. Within these genes, gain of 5hmC is often accompanied by loss of H3K27me3. Enrichment of 5hmC is not associated with substantial DNA demethylation, suggesting that 5hmC is a stable epigenetic mark. Functional perturbation of the H3K27 methyltransferase Ezh2 or of Tet2 and Tet3 leads to defects in neuronal differentiation, suggesting that formation of 5hmC and loss of H3K27me3 cooperate to promote brain development.
哺乳动物的 DNA 甲基化在生殖细胞和植入前胚胎发育过程中高度动态，但在体组织发育过程中相对静态。5-羟甲基胞嘧啶（5hmC）是由 Tet 蛋白氧化 5-甲基胞嘧啶（5mC）产生的，在大脑中含量最丰富，被认为是 5mC 去甲基化的中间产物。我们研究了胚胎小鼠大脑神经发生过程中 5mC 和 5hmC 的模式。5hmC 水平在神经元分化过程中增加。在神经元细胞中，5hmC 不是在增强子处富集，而是优先与激活的神经元功能相关基因的基因体结合。在这些基因中，5hmC 的获得通常伴随着 H3K27me3 的丢失。5hmC 的富集与大量 DNA 去甲基化无关，表明 5hmC 是一种稳定的表观遗传标记。H3K27 甲基转移酶 Ezh2 或 Tet2 和 Tet3 的功能失调会导致神经元分化缺陷，表明 5hmC 的形成和 H3K27me3 的丢失协同促进大脑发育。
