The chromatic loci of H3.3K36M determine the preferential prevalence of K36M mutation at H3.3 in chondroblastomas
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ABSTRACT:
PROVIDER: PRJNA541831 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12952637_1.fastq.gz | Fastqsanger.gz | |||
| SRR12952637_2.fastq.gz | Fastqsanger.gz | |||
| SRR12952638_1.fastq.gz | Fastqsanger.gz | |||
| SRR12952638_2.fastq.gz | Fastqsanger.gz | |||
| SRR12952639_1.fastq.gz | Fastqsanger.gz |
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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: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 unclear how the H3K36M mutation preferentially occurs in the histone H3 variant H3.3 in chondroblastomas. Here, we report that H3.3K36M-, but not H3.1K36M-, mutant cells showed increased colony formation ability and differentiation defects. H3K36 methylations and enhancers were reprogrammed to different status in H3.3K36M- and H3.1K36M-mutant cells. The reprogramming of H3K36 methylation and enhancers was depended on the specific loci at which H3.3K36M and H3.1K36M were incorporated. Moreover, targeting H3K36M-mutant proteins to the chromatin inhibited the H3K36 methylation locally. Taken together, these results highlight the roles of the chromatic localization of H3.3K36M-mutant protein in the reprogramming of the epigenome and the subsequent induction of tumorigenesis, and shed light on the molecular mechanisms by which the H3K36M mutation mainly occurs in histone H3.3 in chondroblastomas.
| S-EPMC7991640 | biostudies-literature
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 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: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: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 variants can effect nucleosome stability or affect histone of DNA modifications. H3.3 is a major H3 histone variant that is incorporated into chromatin outside of S-phase in various eukaryotes. In animals, H3.3 is associated with active transcription and possibly maintenance of transcriptional memory. Plant H3.3, which evolved independently of animal H3.3, is much less well understood. We performed ChIP-chip using chromatin from rosette leaves of 35S:H3.3-YFP plants.
2014-03-10 | E-MTAB-1685 | biostudies-arrayexpress
Project description:Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans, and has been implicated in many important biological processes including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components, or in H3.3 encoding genes, have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3 null mouse models through classical genetic approaches. We found H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres and pericentromeric regions of chromosomes leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. RNA-seq in embryos at E10.5 comparing 3 samples with the following genotype Trp53-/-; H3f3afl/-; H3f3bfl/-; Sox2-CreTg/0 to three samples with the following genotype Trp53-/-; H3f3afl/+; H3f3bfl/+; Sox2-CreTg/0
2015-06-12 | E-GEOD-69771 | biostudies-arrayexpress
Project description:Complex organisms are able to rapidly induce select genes among thousands in response to diverse environmental cues. This occurs in the context of large genomes condensed with histone proteins into chromatin. The macrophage response to pathogen sensing, for example, rapidly engages highly conserved signaling pathways and transcription factors (TF) for coordination of inflammatory gene induction. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general, dynamically regulated chromatin and transcription. However, little is known of how chromatin is regulated at rapidly induced genes and what features of H3.3, conserved from yeast to human, might enable rapid and high-level transcription. The amino-terminus of H3.3 contains a unique serine residue as compared with alanine residues found in “canonical” H3.1/2. We find that this H3.3-specific serine residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along the gene-bodies of rapidly induced response genes in mouse macrophages responding to pathogen sensing. Further, this selective mark of stimulation-responsive genes directly engages histone methyltransferase (HMT) Setd2, a component of the active transcription machinery. Our structure-function studies reveal that a conserved positively charged cleft in Setd2 contacts H3.3S31ph and specifies preferential methylation of H3.3S31ph nucleosomes. We propose that features of H3.3, including H3.3S31ph, engage delegated mechanisms to afford selective and rapid transcription.
2020-05-31 | GSE125159 | GEO