摘要
The euchromatic histone methyltransferase 2 (Ehmt2), aka. G9a, is responsible for methylating histone H3 at lysine 9. However, it is a multifaceted gene whose functions sometimes exceed histone-tail modifications, and the nature and importance of its regulatory effects differ vastly between different tissue systems. A number of lines of evidence hint at its critical role in the developmental biology and tissue biology of mesenchymal tissues. In this work I assessed the role of Ehmt2 in skeletal muscle, adipose tissues, and craniofacial development. Previous publications employing immortalised cell lines have proposed that Ehmt2 is an important inhibitor of myogenic differentiation. In addition to the well-known repressive effects of H3K9 dimethylation, for which Ehmt2 is largely responsible, it was postulated that it can directly methylate MYOD, a master regulator of myogenesis, and lead to repression of myogenic cell differentiation. In a mouse model to validate this, I found conditional knockout muscle stem cells activated, proliferated, and differentiated normally without Ehmt2. Knockout mice under the control of Myod-Cre developed and regenerated normally after acute injury to leg muscle, refuting the previous theory that Ehmt2 is required for myogenesis. The global loss of H3K9 dimethylation in normal myogenesis also signalled that this histone tail modification is largely irrelevant in skeletal muscle. Despite the gene’s dispensability in a number of developmental tissues, Ehmt2-/- mice die early during embryogenesis. In order to uncover the role of Ehmt2 in other mesenchymal tissues, I generated a transgenic mouse line to conditionally delete Ehmt2 during mesoderm and neural crest development. I found that the loss of Ehmt2 in the Pdgfra developmental lineage resulted in striking yet highly reproducible craniofacial malformations. Adipose tissue is also an important topic in the understanding of Ehmt2, especially since previous publications have found its importance in white adipose tissue, and its homologue, Ehmt1/GLP, to be required for brown adipose tissue specification and activation. The PdgfraCre Ehmt2floxed/null mouse model revealed novel in vivo insight for the role in which Ehmt2 limits lipid accumulation and is required for normal brown adipose development.
摘要译文
欧氏族组甲基转移酶2（EHMT2），AKA。 G9A，负责在赖氨酸的甲基化组蛋白H3 9.然而，它是一种多方面基因，其功能有时超过组蛋白尾部修饰，其调节效果的性质和重要性在不同的组织系统之间差异很大。许多证据暗示其在间充质组织的发育生物学和组织生物学中的关键作用。在这项工作中，我评估了EHMT2在骨骼肌，脂肪组织和颅面发育中的作用。以前采用永生化细胞系的出版物提出了EHMT2是肌遗传分化的重要抑制剂。除了具有众所周知的H3K9二甲基化的抑制作用之外，其中EHMT2大部分原理，它假设它可以直接甲酸盐物质，肌生成的主要调节剂，导致抑制肌菌细胞分化。在验证这一点的小鼠模型中，我发现有条件的敲除肌肉干细胞活化，增殖和通常在没有EHMT2的情况下进行分化。在腿部肌肉急性损伤后通常在急性损伤后产生和再生的Myod-Cre的控制，反驳了肌发育所需的理论。在正常骨肉发生中的全局H3K9二甲基化的丧失也表示，这种组蛋白尾部改性在骨骼肌中具有很大不相关的。尽管基因在许多发育组织中的可分配性，但EHMT2 - / - 小鼠在胚胎发生期间早期死亡。为了揭示EHMT2在其他间充质组织中的作用，我在中胚层和神经嵴发育期间产生转基因小鼠线以有条件地删除EHMT2。我发现，PDGFRA发育谱系中的EHMT2的损失导致醒目但高度可重复的颅面畸形。脂肪组织也是理解EHMT2的重要课题，特别是由于以前的出版物发现其在白色脂肪组织中的重要性，并且其同源物，EHMT1 / GLP，棕色脂肪组织规范和活化。 PDGFRARRE EHMT2FLOXED / NULL鼠标模型在体内洞察中揭示了ehmt2限制脂质积累的角色的新颖，是正常棕色脂肪发育所必需的。
Zhang, Regan-Heng. The role of lysine methyltransferase Ehmt2/G9a in mesenchymal development[D]. CA: University of British Columbia, 2017