A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte differentiation
A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte differentiation
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DOI：
10.1080/15592294.2020.1841873
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发表时间：
2020-11-14
期刊：
影响因子：
3.7
通讯作者：
Ishiuchi, Takashi
中科院分区：
文献类型：
--
作者：
Abe, Shusaku;Nagatomo, Hiroaki;Ishiuchi, Takashi
组蛋白赖氨酸-蛋氨酸（K-to-M）突变已被确定为人类癌症的驱动突变。有趣的是，这些“癌组蛋白”突变抑制了组蛋白甲基转移酶的活性。因此，它们可能被用作研究组蛋白修饰作用的通用工具。在本研究中，我们构建了一种内源性H3f3b基因可以诱导H3.3K36M突变的转基因小鼠系。由于H3.3K36M已被确定为人类成软骨细胞瘤的致病突变，我们在小鼠胚胎四肢的软骨细胞谱系中诱导了这种突变。我们发现H3.3K36M导致H3K36me2的整体减少和软骨细胞分化缺陷。重要的是，H3K36me2的减少伴随着正常H3K27me3分布的崩溃。此外，H3K27me3的变化，特别是基因调控元件上H3K27me3的缺失，与一系列对肢体发育重要的基因（包括HoxA簇基因）的错误表达有关。因此，通过体内诱导H3.3K36M突变，我们揭示了在软骨细胞分化和肢体发育过程中维持H3K36me2和H3K27me3之间平衡的重要性。
Histone lysine-to-methionine (K-to-M) mutations have been identified as driver mutations in human cancers. Interestingly, these 'oncohistone' mutations inhibit the activity of histone methyltransferases. Therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we generated a genetically engineered mouse line in which an H3.3K36M mutation could be induced in the endogenous H3f3b gene. Since H3.3K36M has been identified as a causative mutation of human chondroblastoma, we induced this mutation in the chondrocyte lineage in mouse embryonic limbs. We found that H3.3K36M causes a global reduction in H3K36me2 and defects in chondrocyte differentiation. Importantly, the reduction of H3K36me2 was accompanied by a collapse of normal H3K27me3 distribution. Furthermore, the changes in H3K27me3, especially the loss of H3K27me3 at gene regulatory elements, were associated with the mis-regulated expression of a set of genes important for limb development, including HoxA cluster genes. Thus, through the in vivo induction of the H3.3K36M mutation, we reveal the importance of maintaining the balance between H3K36me2 and H3K27me3 during chondrocyte differentiation and limb development.