Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tail
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA682226 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13187562_1.fastq.gz | Fastqsanger.gz | |||
| SRR13187562_2.fastq.gz | Fastqsanger.gz | |||
| SRR13187563_1.fastq.gz | Fastqsanger.gz | |||
| SRR13187563_2.fastq.gz | Fastqsanger.gz | |||
| SRR13187564_1.fastq.gz | Fastqsanger.gz |
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Project description:Deep sequencing of cancer genomes has identified frequent mutation of core histones, termed oncohistones, but the role of some mutants is poorly understood. Here, using fission yeast as a model, we determine the consequences of mutation of histone H3.3 at Gly 34, a site frequently mutated in pediatric cortical high-grade glioma (G34R/V), and in virtually all giant cell tumors of bone (G34W). H3-G34 mutations cause a surprising diversity of outcomes, differentially affecting modification of the nearby H3K36 residue, subtelomeric silencing, genomic stability, sensitivity to irradiation, alkylating agents, hydroxyurea and influencing DNA repair. Since fifteen genes encode H3 isoforms, and only one allele is targeted in cancer, G34R/V/W H3 likely represents a small portion of total cellular H3. Whilst the presence of wild type H3 rescues most G34 mutant phenotypes, hydroxyurea sensitivity, subtelomeric silencing and homologous recombination defects dominate in cells expressing G34R and wild type H3. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in histone H3 and highlight the utility of genetically tractable systems for their analysis.
2021-02-08 | GSE162572 | GEO
Project description:Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair. Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability; sensitivity to irradiation, alkylating agents, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.
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Project description:MMP-9 drives melanomagenic transcription program through histone H3 tail proteolysis
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Project description:Though limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, however the specific genomic sites targeted for H3NT proteolysis and their functional significance of H3NT cleavage remain unknown.We used genome wide RNA-seq approaches to an established cell model of osteoclast differentiation. We discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most of these H3NT-cleaved genes are epigenetically regulated during osteoclastogenesis.We have identified that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). We next studied genomewide mRNA expression in MMP9 knockout cells and its effect in the epigenetic reprogramming of gene pathways required for proficient osteoclastogenesis.
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Project description:Though limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, however the specific genomic sites targeted for H3NT proteolysis and their functional significance of H3NT cleavage remain unknown.We used genome wide Chip-seq (ChIPac-Seq) approaches to an established cell model of osteoclast differentiation. We discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most of these H3NT-cleaved genes are epigenetically regulated during osteoclastogenesis.We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9).Abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. In summary our results support the necessity of MMP-9-dependent H3NT proteolysis in the epigenetic reprogramming of gene pathways required for proficient osteoclastogenesis.
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Project description:The closely related replicative H3 and non-replicative H3.3 variants show specific requirement during development in vertebrates. Whether it involves distinct mode of deposition or unique roles once incorporated into chromatin remains unclear. To disentangle the two aspects, we took advantage of the Xenopus early development combined with chromatin assays. We systematically mutated H3.3 at each four residues that differ from H3.2 and tested their ability to rescue developmental defects due to endogenous H3.3 depletion. Surprisingly, all H3.3 mutated variants functionally complemented endogenous H3.3, regardless of their incorporation pathways, except for one residue, the serine at position 31. The phosphorylation at this unique residue occurs onto chromatin with a peak in late mitosis, and depends on the networks of cell cycle kinases. Notably, while the alanine substitution failed to rescue H3.3 depletion, a phosphomimic residue sufficed. Based on proteomics studies with histone peptides and Xenopus extracts, we find that the phosphomimic histone mutant attracts transcription related factors. Furthermore, we evidence a crosstalk whereby phosphorylation on H3.3S31 favors H3.3K27ac. At gastrulation, we conclude that the critical importance of the H3.3S31 residue is independent of the variant incorporation pathway. It rather reflects a signaling role engaging key binding partners and crosstalks on neighboring amino acids. We discuss how this single evolutionary conserved residue conveys both in interphase and mitosis unique properties for this variant in vertebrates during cell cycle and cell fate commitment.
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Project description:In budding yeast, telomeres and the mating type (HM) loci are found in a heterochromatin-like silent structure initiated by Rap1 and extended by the interaction of Sir (Silencing Information Regulator) proteins with histones. Binding data demonstrate that both the H3 and H4 N terminal domains required for silencing in vivo interact directly with Sir3 and Sir4 in vitro. The role of H4 lysine 16 deacetylation is well established in Sir3 protein recruitment, however that of the H3 N terminal tail has remained unclear. In order to characterize the role of H3 in silent chromatin formation and compare it to H4 we have generated comprehensive high resolution genome-wide binding maps of heterochromatin proteins. We find that H4 lysine 16 deacetylation is required for the recruitment and spreading of heterochromatin proteins at all telomeres and HM loci. In contrast the H3 N terminus is required for neither recruitment nor spreading of Sir proteins. Instead, deletion of the H3 tail leads to increased accessibility within heterochromatin of an ectopic bacterial dam methylase and the decreased mobility of an HML heterochromatic fragment in sucrose gradients. These findings indicate an altered chromatin structure. We propose that Sir proteins recruited by the H4 tail then interact with the H3 tail to form a higher order silent chromatin structure.
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Project description:Using histone H3 mutants designed so that they can only form a heterodimer, we studied the gene expression in a collection of mutants, comparing mutations to one histone H3 tail of a nucleosome compared to two histone H3 tails of a nucleosome.
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