The H3.3K27M oncohistone antagonizes reprogramming in Drosophila
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ABSTRACT:
PROVIDER: PRJNA679825 | ENA |
REPOSITORIES: ENA
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Project description:Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In some cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that expression of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 domains are globally reduced with oncohistone expression, suggesting that previous developmental programs must be silenced for effective transformation. Strikingly, mis-expressed Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb Repressive Complex 1 components. Our results imply that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.
2021-06-15 | GSE161919 | GEO
Project description: Not available
| S-EPMC8320987 | biostudies-literature
Project description:Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Tumor cells carrying the mutation show a dramatic decrease in H3K27me3 levels due to physical inhibition of PRC2 methyltransferase activity. Here we use a C. elegans model to quantify the antagonistic effects of the H3.3K27M oncohistone on H3K27 trimethylation genome wide. We demonstrate that PRC2 is locally both simulated by H3K27me3 and inhibited by the oncohistone in a concentration-dependent manner.
2019-04-26 | GSE117531 | GEO
Project description:Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Tumor cells carrying the mutation show a dramatic decrease in H3K27me3 levels due to physical inhibition of PRC2 methyltransferase activity. Here we use a C. elegans model to quantify the antagonistic effects of the H3.3K27M oncohistone on H3K27 trimethylation genome wide. We demonstrate that PRC2 is locally both simulated by H3K27me3 and inhibited by the oncohistone in a concentration-dependent manner.
2019-04-26 | GSE117471 | GEO
Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.
2017-10-27 | GSE100826 | GEO
Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.
2017-10-27 | GSE95168 | GEO
Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.
2017-10-27 | GSE95167 | GEO
Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion of pediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.
2017-10-27 | GSE95277 | GEO
Project description:Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis. We performed chromatin-immunoprecipitation of H3K27me3, H3K4me3, and EZH2 in SF7761 and NSC cell lines. And do RNA-seq in SF7761, SF8828 and NSC cell lines. SF7761 and SF8628 cell lines from patients harboring the histone H3.3 K27M mutation were obtained from Hashizume et al. (2012). NSCs (N7800-100) were purchased from Invitrogen and cultured and maintained in NSC medium (A10509-01, StemPro NSC SFM, Invitrogen).
2014-09-20 | E-GEOD-61586 | biostudies-arrayexpress
Project description:Patients with diffuse midline gliomas-H3K27-altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 co-localizes with SOX10 at gene regulatory elements (GRE) to control the expression of genes involved in cell growth and extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG.
2022-09-02 | GSE185280 | GEO