Developmental and Molecular Pathways, Cambridge, MA 02139, USA.
Stem Cells. 2010 Feb;28(2):201-12. doi: 10.1002/stem.278.
Dynamic regulation of histone methylation by methyltransferases and demethylases plays a central role in regulating the fate of embryonic stem (ES) cells. The histone H3K9 methyltransferase KMT1E, formerly known as ESET or Setdb1, is essential to embryonic development as the ablation of the Setdb1 gene results in peri-implantation lethality and prevents the propagation of ES cells. However, Setdb1-null blastocysts do not display global changes in H3K9 methylation or DNA methylation, arguing against a genome-wide defect. Here we show that conditional deletion of the Setdb1 gene in ES cells results in the upregulation of lineage differentiation markers, especially trophectoderm-specific factors, similar to effects observed upon loss of Oct3/4 expression in ES cells. We demonstrate that KMT1E deficiency in ES cells leads to a decrease in histone H3K9 methylation at and derepression of trophoblast-associated genes such as Cdx2. Furthermore, we find genes that are derepressed upon Setdb1 deletion to overlap with known targets of polycomb mediated repression, suggesting that KMT1E mediated H3K9 methylation acts in concert with polycomb controlled H3K27 methylation. Our studies thus demonstrate an essential role for KMT1E in the control of developmentally regulated gene expression programs in ES cells.
组蛋白甲基转移酶和去甲基化酶对组蛋白甲基化的动态调控在调节胚胎干细胞（ES 细胞）命运中起着核心作用。组蛋白 H3K9 甲基转移酶 KMT1E（以前称为 ESET 或 Setdb1）对胚胎发育至关重要，因为 Setdb1 基因的缺失会导致植入前致死，并阻止 ES 细胞的增殖。然而，Setdb1 基因缺失的囊胚并没有显示出 H3K9 甲基化或 DNA 甲基化的全局变化，这表明不存在全基因组缺陷。在这里，我们表明 ES 细胞中 Setdb1 基因的条件缺失导致谱系分化标记物的上调，特别是滋养外胚层特异性因子，类似于 ES 细胞中 Oct3/4 表达缺失所观察到的效应。我们证明 ES 细胞中 KMT1E 的缺乏导致组蛋白 H3K9 甲基化在和滋养层相关基因如 Cdx2 的去抑制。此外，我们发现 Setdb1 缺失后去抑制的基因与已知的多梳抑制靶基因重叠，表明 KMT1E 介导的 H3K9 甲基化与多梳控制的 H3K27 甲基化协同作用。我们的研究因此证明了 KMT1E 在 ES 细胞中发育调控基因表达程序的控制中的重要作用。
