A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation
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ABSTRACT:
PROVIDER: PRJNA631838 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11774232.fastq.gz | Fastqsanger.gz | |||
| SRR11774233.fastq.gz | Fastqsanger.gz | |||
| SRR11774234.fastq.gz | Fastqsanger.gz | |||
| SRR11774235.fastq.gz | Fastqsanger.gz | |||
| SRR11774236.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-11-01 | GSE150353 | GEO
Project description: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, and, therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we created a conditional knock-in mouse line in which a H3.3K36M mutation can be induced in the endogenous H3.3 gene. Since the H3.3K36M mutation 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 global reduction of 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 misregulated expression of a set of genes important for limb development including HoxA cluster genes. Thus, taking advantage of the in vivo induction of H3.3K36M mutation, we reveal the importance of a counterbalance between H3K36me2 and H3K27me3 for chondrocyte differentiation and limb development.
2020-11-01 | GSE150352 | GEO
Project description: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, and, therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we created a conditional knock-in mouse line in which a H3.3K36M mutation can be induced in the endogenous H3.3 gene. Since the H3.3K36M mutation 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 global reduction of 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 misregulated expression of a set of genes important for limb development including HoxA cluster genes. Thus, taking advantage of the in vivo induction of H3.3K36M mutation, we reveal the importance of a counterbalance between H3K36me2 and H3K27me3 for chondrocyte differentiation and limb development.
2020-11-01 | GSE150351 | GEO
Project description:A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [ChIP-seq]
| PRJNA631842 | ENA
Project description:A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [RNA-seq]
| PRJNA631841 | ENA
Project description:Over 90% of chondroblastomas contain a heterozygous mutation replacing lysine 36 with methionine (K36M) in the histone H3 variant H3.3. The role of the H3.3K36M mutation in tumorigenesis of this typically benign bone tumor with high recurrence rates is unknown. Here, we show that H3K36 di- and tri-methylation (me2 and me3) levels are reduced globally in chondroblastomas, as well as in chondrocytes stably expressing the H3.3K36M mutation because the H3.3M36 mutation protein inhibits the activity of lysine methyl transferases, MMSET and SetD2. Remarkably, at gene bodies, H3K36me2 increases and H3K36me3 decreases, which correlates with elevated and reduced expression of the underlying genes, respectively. Genes with altered H3K36me2/me3 and gene expression are associated with cancer pathways and chondrocyte differentiation. Chondrocytes harboring the H3.3K36M mutation exhibit cancer-associated cellular phenotypes and delayed chondrocyte differentiation associated with reduced Bmp2 and Runx2 expression. Exogenous Bmp2 partially rescued the delays in chondrocyte differentiation. Thus, H3.3K36M mutant proteins dominantly reprogram H3K36me2/me3 and chondrocyte gene expression, inhibiting terminal chondrocyte differentiation and contributing to tumorigenesis.
2016-10-06 | GSE75234 | GEO
Project description: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.
| S-EPMC8510613 | biostudies-literature
Project description:The histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it’s still unknown how the H3K36M mutation preferentially happens at the histone H3 variant H3.3. Here we report that, H3.3K36M mutation, but not H3.1K36M mutation, promoted increased colony formation and defects in differentiation. The reduction of H3K36 methylation and initiation of new H3K36 methylation sites in chromatin is dependent on the incorporation loci of H3.3K36M and H3.1K36M. Moreover, while both H3.3K36M and H3.1K36M mutation inactivated the enhancers, only H3.3K36M mutation changed the super enhancers associated with genes in general development, depending on the chromatic incorporation loci of H3.3K36M mutant proteins. Together, this study highlights the roles of the chromatic localization of H3.3K36M mutant proteins in the reprograming of epigenome and subsequent induction of tumorigenesis, and sheds light on the molecular mechanisms how H3K36M mutation mainly occurs at histone H3.3 in chondroblastomas.
2019-05-09 | GSE130858 | GEO
Project description:Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.
2024-08-01 | GSE270501 | GEO
Project description:Cranial neural crest (NCC)-derived chondrocyte precursors undergo a dynamic differentiation and maturation process to establish a scaffold for subsequent bone formation, alterations in which contribute to congenital birth defects. Here, we demonstrate that transcription factor and histone methyltransferase proteins Prdm3 and Prdm16 control the differentiation switch of cranial NCCs to craniofacial cartilage. Loss of either results in hypoplastic and unorganized chondrocytes due to impaired cellular orientation and polarity. We show that PRDMs regulate cartilage differentiation by controlling the timing of Wnt/β-catenin activity in strikingly different ways: prdm3 represses while prdm16 activates global gene expression, though both by regulating Wnt enhanceosome activity and chromatin accessibility. Finally, we show that manipulating Wnt/β-catenin signaling pharmacologically or generating prdm3-/-;prdm16-/- double mutants rescues craniofacial cartilage defects. Our findings reveal upstream regulatory roles for Prdm3 and Prdm16 in cranial NCCs to control Wnt/β-catenin transcriptional activity during chondrocyte differentiation to ensure proper development of the craniofacial skeleton.
2022-02-08 | GSE175767 | GEO