A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte differentiation
| Autor: | Hiroyuki Sasaki, Hiroaki Nagatomo, Takashi Ishiuchi, Shusaku Abe |
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| Přispěvatelé: | 伊藤, 隆司, 目野, 主税, 中島, 康晴 |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Lineage (genetic) Biology medicine.disease_cause Chondrocyte Histones Mice 03 medical and health sciences Histone H3 Chondrocytes 0302 clinical medicine medicine Animals Limb development Molecular Biology Gene Mutation DNA Methylation Cell biology Histone Code 030104 developmental biology Histone medicine.anatomical_structure 030220 oncology & carcinogenesis Histone methyltransferase biology.protein Research Paper |
| Zdroj: | Epigenetics |
| ISSN: | 1559-2308 1559-2294 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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