Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Epigenetics Chromatin. 2009 Apr 6;2(1):5. doi: 10.1186/1756-8935-2-5.
Histone methylation is thought to be central to the epigenetic mechanisms that maintain and confine cellular identity in multi-cellular organisms. To examine epigenetic roles in cellular homeostasis, we conditionally mutated the histone 3 lysine 4 methyltransferase, Mll2, in embryonic stem (ES) cells, during development and in adult mice using tamoxifen-induced Cre recombination.
In ES cells, expression profiling unexpectedly revealed that only one gene, Magoh2, is dependent upon Mll2 and few other genes were affected. Loss of Mll2 caused loss of H3K4me3 at the Magoh2 promoter and concomitant gain of H3K27me3 and DNA methylation. Hence Mll2, which is orthologous to Drosophila Trithorax, is required to prevent Polycomb-Group repression of the Magoh2 promoter, and repression is further accompanied by DNA methylation. Early loss of Mll2 in utero recapitulated the embryonic lethality found in Mll2-/- embryos. However, loss of Mll2 after E11.5 produced mice without notable pathologies. Hence Mll2 is not required for late development, stem cells or homeostasis in somatic cell types. However it is required in the germ cell lineage. Spermatogenesis was lost upon removal of Mll2, although spermatogonia A persisted.
These data suggest a bimodal recruit and maintain model whereby Mll2 is required to establish certain epigenetic decisions during differentiation, which are then maintained by redundant mechanisms. We also suggest that these mechanisms relate to the epigenetic maintenance of CpG island promoters.
组蛋白甲基化被认为是维持多细胞生物细胞身份的表观遗传机制的核心。为了研究细胞稳态中的表观遗传作用，我们使用他莫昔芬诱导的 Cre 重组在胚胎干细胞 (ES) 中、在发育过程中和成年小鼠中条件性突变组蛋白 3 赖氨酸 4 甲基转移酶 Mll2。
在 ES 细胞中，表达谱分析出人意料地表明，只有一个基因 Magoh2 依赖于 Mll2，其他几个基因受影响较小。Mll2 的缺失导致 Magoh2 启动子处的 H3K4me3 丢失，同时 H3K27me3 和 DNA 甲基化增加。因此，与果蝇 Trithorax 同源的 Mll2 被需要防止 Polycomb 组抑制 Magoh2 启动子，抑制伴随着 DNA 甲基化。Mll2 在子宫内的早期缺失重现了在 Mll2-/- 胚胎中发现的胚胎致死性。然而，E11.5 后 Mll2 的缺失产生了没有明显病理的小鼠。因此，Mll2 不是体细胞类型中晚期发育、干细胞或稳态所必需的。然而，它在生殖细胞谱系中是必需的。Mll2 的缺失导致精子发生丢失，尽管精原细胞 A 仍然存在。
这些数据表明存在一种双峰招募和维持模型，其中 Mll2 在分化过程中需要建立某些表观遗传决定，然后由冗余机制维持这些决定。我们还表明，这些机制与 CpG 岛启动子的表观遗传维持有关。
