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MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner
Nature Genetics ( IF 30.8 ) Pub Date : 2023-04-03 , DOI: 10.1038/s41588-023-01356-4
Guojia Xie 1 , Ji-Eun Lee 1 , Anna D Senft 2 , Young-Kwon Park 1 , Younghoon Jang 1 , Shreeta Chakraborty 3 , Joyce J Thompson 3 , Kaitlin McKernan 1 , Chengyu Liu 4 , Todd S Macfarlan 2 , Pedro P Rocha 3, 5 , Weiqun Peng 6 , Kai Ge 1
Affiliation  

H3K4me1 methyltransferases MLL3 (KMT2C) and MLL4 (KMT2D) are critical for enhancer activation, cell differentiation and development. However, roles of MLL3/4 enzymatic activities and MLL3/4-mediated enhancer H3K4me1 in these processes remain unclear. Here we report that constitutive elimination of both MLL3 and MLL4 enzymatic activities prevents initiation of gastrulation and leads to early embryonic lethality in mice. However, selective elimination of MLL3/4 enzymatic activities in embryonic, but not extraembryonic, lineages leaves gastrulation largely intact. Consistent with this, embryonic stem cells (ESCs) lacking MLL3/4 enzymatic activities can differentiate toward the three embryonic germ layers but show aberrant differentiation to extraembryonic endoderm (ExEn) and trophectoderm. The failure in ExEn differentiation can be attributed to markedly reduced enhancer-binding of the lineage-determining transcription factor GATA6. Furthermore, we show that MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation during ESC differentiation. Together, our findings suggest a lineage-selective, but enhancer activation-independent, role of MLL3/4 methyltransferase activities in early embryonic development and ESC differentiation.



中文翻译:

MLL3/MLL4甲基转移酶活性以谱系选择性方式控制早期胚胎发育和胚胎干细胞分化

H3K4me1 甲基转移酶 MLL3 (KMT2C) 和 MLL4 (KMT2D) 对于增强子激活、细胞分化和发育至关重要。然而,MLL3/4 酶活性和 MLL3/4 介导的增强子 H3K4me1 在这些过程中的作用仍不清楚。在此,我们报告,MLL3 和 MLL4 酶活性的组成型消除可阻止原肠胚形成的启动并导致小鼠早期胚胎死亡。然而,选择性消除胚胎谱系中的 MLL3/4 酶活性(而非胚胎外谱系)可使原肠胚形成基本保持完整。与此一致的是,缺乏 MLL3/4 酶活性的胚胎干细胞 (ESC) 可以分化为三个胚胎胚层,但会异常分化为胚外内胚层 (ExEn) 和滋养外胚层。ExEn 分化的失败可归因于谱系决定转录因子 GATA6 的增强子结合显着减少。此外,我们发现 MLL3/4 催化的 H3K4me1 对于 ESC 分化过程中的增强子激活来说在很大程度上是可有可无的。总之,我们的研究结果表明 MLL3/4 甲基转移酶活性在早期胚胎发育和 ESC 分化中具有谱系选择性但增强子激活无关的作用。

更新日期:2023-04-03
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