Genome wide methylation profliling of pediatric glioblastomas.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55712 | GEO | 2014/03/09
SECONDARY ACCESSION(S): PRJNA240635
REPOSITORIES: GEO
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Project description:Genome wide DNA methylation profiling of WT, K27M, G34R and IDH1glioblastomas Bisulphite converted DNA from 38 WT, 28 K27M, 17 IDH1 AND 15 G34R samples hybridised to the Illumina 450k Human Methylation Beadchip
2014-03-09 | E-GEOD-55712 | biostudies-arrayexpress
Project description:We identified that RACK7 recognizes the histone H3.3G34R mutaion in vitro and in vivo. In order to explore the function of RACK7 and H3.3G34R mutaion, we used three pediatric glioblastomas(pGBM) cell lines. SJ-HGGx6c(R6) and SJ-HGGx42c(R42) have heterozygous G34R mutation, while SJ-HGGx39c(WT39) has wildtype H3F3A, which encodes H3.3. We next corrected H3.3G34R in R6 and R42 cells to wildtype H3.3 by CRISPR/Cas9 mediated knock-in, and knocked out RACK7 in R6 and R42 cells by CRISPR/Cas9. Finaly, we performed genome-wide transcriptomic analysis in these cell lines by RNA-seq analysis.
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Project description:We identified that RACK7 recognizes the histone H3.3G34R mutaion in vitro. In order to determine the interaction between RACK7 and H3.3G34R mutaion in cells, we used three pediatric glioblastoma (pGBM) cell lines. SJ-HGGx6c(R6) and SJ-HGGx42c(R42) have heterozygous G34R mutation, while SJ-HGGx39c(WT39) has wildtype H3F3A, which encodes H3.3, and we also corrected H3.3G34R in R6 and R42 cells to wildtype H3.3 by CRISPR/Cas9 mediated knock-in. Finally, we performed RACK7 ChIP-seq in these cell lines to explore the function of RACK7 and H3.3G34R mutation.
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Project description:High-grade pediatric gliomas often contain histone H3.3 mutations, but open questions remain about oncogenic mechanisms. To address this gap, we performed ‘reciprocal gene editing’ using CRISPR-Cas9 to introduce H3.3 mutations (K27M, G34R) into H3.3-wildtype brain and glioma cells, while in parallel reverting pre-existing K27M mutations in glioma cells back to wildtype. Analyses of our reciprocally-edited cells indicate that H3.3 mutation leads to specific transcriptomic and epigenetic events, and associated cell biological changes including in xenograft assays. We used these data and the reciprocally-edited cells to screen selected drugs and identify specific putative treatments that are mutant H3.3-specific. Overall, reciprocal gene editing provides new insights into mutant H3.3 oncogenic mechanisms and more broadly may prove useful for studying other cancer-associated mutations.
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Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R mutant histone H3.3. H3.3-G34R mutants are common in tumors additionally mutant for p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, but minimally affects transcriptional control. H3-G34R mutants exhibit genomic instability and increased replicative stress including slowed replication fork restart although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and on damage have altered HR protein dynamics suggestive that H3-G34R slows resolution of HR-mediated repair. In summary our analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.
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Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R mutant histone H3.3. H3.3-G34R mutants are common in tumors additionally mutant for p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, but minimally affects transcriptional control. H3-G34R mutants exhibit genomic instability and increased replicative stress including slowed replication fork restart although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and on damage have altered HR protein dynamics suggestive that H3-G34R slows resolution of HR-mediated repair. In summary our analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.
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Project description:Sequencing of paediatric gliomas has identified two common substitution mutations (K27M and G34R) in genes encoding histone H3.3. We introduced a single-copy H3.3 G34R targeted mutation in mouse ES cells and observed gains in H3K36me3 and H3K9me3 across the genome. Altered chromatin profiles correlated with enrichment of KDM4 A/B/C, a histone lysine (K9/K36) demethylase. RNA-seq of H3.3 G34R mutant showed disrupted gene expression patterns which also correlated with KDM4 enrichment. Expression of a single copy of H3.3 G34R at endogenous levels was sufficient to genocopy KDM4 triple-KO cells as determined by ChIP-seq and RNA-seq.
2018-07-08 | GSE106203 | GEO
Project description:Sequencing of paediatric gliomas has identified two common substitution mutations (K27M and G34R) in genes encoding histone H3.3. We introduced a single-copy H3.3 G34R targeted mutation in mouse ES cells and observed gains in H3K36me3 and H3K9me3 across the genome. Altered chromatin profiles correlated with enrichment of KDM4 A/B/C, a histone lysine (K9/K36) demethylase. RNA-seq of H3.3 G34R mutant showed disrupted gene expression patterns which also correlated with KDM4 enrichment. Expression of a single copy of H3.3 G34R at endogenous levels was sufficient to genocopy KDM4 triple-KO cells as determined by ChIP-seq and RNA-seq.
2018-07-08 | GSE106204 | GEO
Project description:Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. While cytogenetic abnormalities have been well characterized in this disease, aberrant epigenetic events such as DNA hypermethylation have not been described in genome-wide studies. We have analyzed the methylation status of 25,500 promoters in normal skeletal muscle, and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. We identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Genes involved in tissue development, differentiation, and oncogenesis such as DNAJA4, HES5, IRX1, BMP8A, GATA4, GATA6, ALX3, and P4HTM were hypermethylated in both RMS cell lines and primary samples, implicating aberrant DNA methylation in the pathogenesis of rhabdomyosarcoma. Furthermore, cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.
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Project description:Genome wide DNA methylation profiling of pediatric acute myeloid leukemia obtained from bone marrow. The Illumina EPIC methylation beadchip array was used to obtain DNA methylation profiles across approximately 850,000 CpG dinucleotide methylation loci in DNA isolated from leukemia. Samples include 64 patients.
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