The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

Lim, Jinyeong; Park, Joo Hyun; Baude, Annika; Yoo, Yeongran; Lee, Yeon Kyu; Schmidt, Christopher R.; Park, Jong Bae; Fellenberg, Jörg; Zustin, Josef; Haller, Florian; Krücken, Irene; Kang, Hyun Guy; Plass, Christoph; Lindroth, Anders M.

doi:10.1038/s41598-017-13887-y

Cited by 44 publications

(50 citation statements)

References 53 publications

(66 reference statements)

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“…We also reported that Rpp29 depletion increases H3.3 chromatin deposition and sense (S) and AS RNA levels, which suggests that an RNase P variant represses H3.3 chromatin assembly and transcription. Consistent with our results, a recent study identified RNA proteins, including RPLs and splicing factors, as H3.3-interacting factors (40). This study also showed that H3.3(G34W) increases chromatin compaction and causes aberrant RNA processing.…”

supporting

confidence: 92%

“…Several, including the GCTB mutation, G34W, increase the affinity for Rpp29. Of interest, H3.3(G34W) has been reported to down-regulate transcription and increase chromatin compaction (40). Because we show that Rpp29 promotes heterochromatic PTM deposition, it is possible that H3.3(G34W) promotes tumorigenesis by enhancing the gene-silencing function of Rpp29.…”

Section: Rpp29 Regulates H33 Through Transcriptional Mechanismsmentioning

confidence: 68%

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Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Shastrula

Lund

Garcia

et al. 2018

Journal of Biological Chemistry

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The histone H3 variant H3.3 is a highly conserved and dynamic regulator of chromatin organization. Therefore, fully elucidating its nucleosome incorporation mechanisms is essential to understanding its functions in epigenetic inheritance. We previously identified the RNase P protein subunit, Rpp29, as a repressor of H3.3 chromatin assembly. Here, we use a biochemical assay to show that Rpp29 interacts with H3.3 through a sequence element in its own N terminus, and we identify a novel interaction with histone H2B at an adjacent site. The fact that archaeal Rpp29 does not include this N-terminal region suggests that it evolved to regulate eukaryote-specific functions. Oncogenic H3.3 mutations alter the H3.3-Rpp29 interaction, which suggests that they could dysregulate Rpp29 function in chromatin assembly. We also used KNS42 cells, an H3.3(G34V) pediatric high-grade glioma cell line, to show that Rpp29 1) represses H3.3 incorporation into transcriptionally active protein-coding, rRNA, and tRNA genes; 2) represses mRNA, protein expression, and antisense RNA; and 3) represses euchromatic post-translational modifications (PTMs) and promotes heterochromatic PTM deposition ( histone H3 Lys-9 trimethylation (H3K9me3) and H3.1/2/3K27me3). Notably, we also found that K27me2 is increased and K36me1 decreased on H3.3(G34V), which suggests that Gly-34 mutations dysregulate Lys-27 and Lys-36 methylation in The fact that Rpp29 represses H3.3 chromatin assembly and sense and antisense RNA and promotes H3K9me3 and H3K27me3 suggests that Rpp29 regulates H3.3-mediated epigenetic mechanisms by processing a transcribed signal that recruits H3.3 to its incorporation sites.

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supporting

confidence: 92%

Section: Rpp29 Regulates H33 Through Transcriptional Mechanismsmentioning

confidence: 68%

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Shastrula

Lund

Garcia

et al. 2018

Journal of Biological Chemistry

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“…For GCTB, the genes undergoing a change upon redistribution of the H3K36me3 marks as a result of the H3F3A G34W/L mutations remain to be identified. Changes that are observed in primary GCTB cells harbouring a G34W mutation are increased proliferation, migration and colony formation capacity as compared to wild-type counterparts [55,56]. Furthermore, splicing aberrations and alternative transcription start sites are frequently observed in H3F3A G34W-mutated cells, suggesting an alteration in the RNA processing pathway [55].…”

Section: Idh1 R132hmentioning

confidence: 99%

“…Changes that are observed in primary GCTB cells harbouring a G34W mutation are increased proliferation, migration and colony formation capacity as compared to wild-type counterparts [55,56]. Furthermore, splicing aberrations and alternative transcription start sites are frequently observed in H3F3A G34W-mutated cells, suggesting an alteration in the RNA processing pathway [55]. Future studies are needed to elucidate which genes and signalling pathways are affected by the H3F3A G34 mutationdriven epigenetic alterations.…”

Section: Idh1 R132hmentioning

confidence: 99%

Mutation-driven epigenetic alterations as a defining hallmark of central cartilaginous tumours, giant cell tumour of bone and chondroblastoma

et al. 2019

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Recently, specific driver mutations were identified in chondroblastoma, giant cell tumour of bone and central cartilaginous tumours (specifically enchondroma and central chondrosarcoma), sharing the ability to induce genome-wide epigenetic alterations. In chondroblastoma and giant cell tumour of bone, the neoplastic mononuclear stromal-like cells frequently harbour specific point mutations in the genes encoding for histone H3.3 (H3F3A and H3F3B). The identification of these driver mutations has led to development of novel diagnostic tools to distinguish between chondroblastoma, giant cell tumour of bone and other giant cell containing tumours. From a biological perspective, these mutations induce several global and local alterations of the histone modification marks. Similar observations are made for central cartilaginous tumours, which frequently harbour specific point mutations in the metabolic enzymes IDH1 or IDH2. Besides an altered methylation pattern on histones, IDH mutations also induce a global DNA hypermethylation phenotype. In all of these tumour types, the mutation-driven epigenetic alterations lead to a highly altered transcriptome, resulting for instance in alterations in differentiation. These genomic alterations have diagnostic impact. Further research is needed to identify the genes and signalling pathways that are affected by the epigenetic alterations, which will hopefully lead to a better understanding of the biological mechanism underlying tumourigenesis.

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“…Together we collected data from analysis platforms with the ambition to understand the function of H3.3 in cancer ( Fig. 1c ), which in part has been described in a previous publication 7 .…”

Section: Background and Summarymentioning

confidence: 99%

Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3

Lim

Park²,

Baude

et al. 2018

Sci Data

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Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.

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The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

Cited by 44 publications

References 53 publications

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Rpp29 regulates histone H3.3 chromatin assembly through transcriptional mechanisms

Mutation-driven epigenetic alterations as a defining hallmark of central cartilaginous tumours, giant cell tumour of bone and chondroblastoma

Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3

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