小柯机器人

美国国立卫生研究院Kai Ge团队发现，MLL3/MLL4甲基转移酶的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。相关论文于2023年4月3日在线发表在《自然—遗传学》杂志上。

研究人员发现，MLL3和MLL4酶活性的组成性消除阻止了小鼠原肠运动的启动，并导致早期胚胎死亡。然而，选择性地消除MLL3/4在胚胎中的酶活性，而不是在胚胎外谱系中的酶活性，则使原肠运动基本保持完整。与此相一致的是，缺乏MLL3/4酶活性的胚胎干细胞（ESC）可以向三个胚胎生殖层分化，但显示出向胚外内胚层（ExEn）和滋养层的反常分化。胚胎外胚层分化的失败可归因于决定胚胎系的转录因子GATA6的增强子结合明显减少。此外，研究人员显示MLL3/4催化的H3K4me1在ESC分化过程中对增强子的激活基本不需要。

总之，这些研究结果表明，MLL3/4甲基转移酶在早期胚胎发育和胚胎干细胞分化过程中具有谱系选择性作用，但不依赖于增强子的激活。

据了解，H3K4me1甲基转移酶MLL3（KMT2C）和MLL4（KMT2D）对于增强子的激活、细胞分化和发育至关重要。然而，MLL3/4的酶活性和MLL3/4介导的增强子H3K4me1在这些过程中的作用仍不清楚。

附：英文原文

Title: MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner

Author: Xie, Guojia, Lee, Ji-Eun, Senft, Anna D., Park, Young-Kwon, Jang, Younghoon, Chakraborty, Shreeta, Thompson, Joyce J., McKernan, Kaitlin, Liu, Chengyu, Macfarlan, Todd S., Rocha, Pedro P., Peng, Weiqun, Ge, Kai

Issue&Volume: 2023-04-03

Abstract: 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.

DOI: 10.1038/s41588-023-01356-4

Source: https://www.nature.com/articles/s41588-023-01356-4

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