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Published on: January 26, 2018
A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte
Shusaku Abe1, Hiroaki Nagatomo2,3, Hiroyuki Sasaki1
1Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Abstract:
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.
Insights
Histone H3.3K36M mutations disrupt chondrocyte differentiation by altering histone methylation patterns. This research reveals the critical balance between H3K36me2 and H3K27me3 for limb development.
Area of Science:
- Epigenetics
- Developmental Biology
- Cancer Biology
Background:
- Histone lysine-to-methionine (K-to-M) mutations, known as oncohistone mutations, are drivers in human cancers.
- These mutations inhibit histone methyltransferases, offering tools to study histone modification roles.
Purpose of the Study:
- To investigate the in vivo effects of the H3.3K36M mutation on chondrocyte differentiation and limb development.
- To elucidate the interplay between H3K36me2 and H3K27me3 in response to the H3.3K36M mutation.
Main Methods:
- Generated a genetically engineered mouse model with inducible H3.3K36M mutation in the H3f3b gene.
- Induced the H3.3K36M mutation in the chondrocyte lineage of mouse embryonic limbs.
Main Results:
- H3.3K36M mutation caused a global reduction in H3K36me2 and impaired chondrocyte differentiation.
- H3K36me2 reduction led to altered H3K27me3 distribution, particularly at gene regulatory elements.
- Changes in H3K27me3 correlated with mis-regulated expression of key limb development genes, including HoxA clusters.
Conclusions:
- The H3.3K36M mutation disrupts the balance between H3K36me2 and H3K27me3.
- Maintaining this epigenetic balance is crucial for normal chondrocyte differentiation and embryonic limb development.
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