Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA769715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16258994_1.fastq.gz | Fastqsanger.gz | |||
| SRR16258994_2.fastq.gz | Fastqsanger.gz | |||
| SRR16258995_1.fastq.gz | Fastqsanger.gz | |||
| SRR16258995_2.fastq.gz | Fastqsanger.gz | |||
| SRR16258996_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism responds to and governs the loss-of-function oncohistone remains unclear. Here, we generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B level, disrupted cell divisions, and caused animal sterility. Our genetic screens identified mutations defective in a histone H3-H4 chaperone UNC-85 as suppressors that recovered H2B 3KO fertility. We found that unc-85 mutations reduced chromatin H3-H4 levels and that inhibiting other H3-H4 chaperones or H3-H4 histones also rescued H2B 3KO sterility. The oncohistone H2BE76K mutation disrupts the H2B-H4 interface and causes nucleosome instability, and we showed that blocking H3-H4 chaperones restored cell division defects in C. elegans or human cells carrying H2BE76K. Thus, our results indicate that reducing chromatin H3-H4 rescues H2B loss and suggest that inhibiting H3-H4 chaperones may be a therapeutic strategy to treat cancers resulting from loss-of-function H2B oncohistone.
2022-04-03 | GSE185582 | GEO
Project description:The H3K27M oncogenic histone (oncohistone) mutation drives ~80% of incurable childhood brain tumors known as diffuse midline gliomas (DMGs). The major molecular feature of H3K27M mutant DMGs is a global loss of H3K27 tri-methylation (H3K27me3), a phenotype conserved in Caenorhabditis elegans (C. elegans). Here we perform unbiased genome-wide suppressor screens in C. elegans expressing H3K27M, and isolate 20 suppressors, all of which at least partially restore H3K27me3. 19/20 suppressor mutations map to the same histone H3.3 gene in which the K27M mutation was originally introduced. Most of these create single amino acid substitutions between residues R26-Y54, which do not disrupt oncohistone expression. Rather, they are predicted to impair interactions with the Polycomb Repressive Complex 2 (PRC2) and are functionally conserved in human cells. Further, we mapped a single extragenic H3K27M suppressor to ubc-20, an E2 ubiquitin conjugating enzyme, whose loss rescued H3K27me3 to nearly 50% wild-type levels despite continued oncohistone expression and chromatin incorporation. We demonstrate that ubc-20 is the major enzyme responsible for generating di-ubiquitinated histone H2B. Our study provides in vivo support for existing models of PRC2 inhibition via direct oncohistone contact, and suggests that the effects of H3K27M may be modulated by H2B ubiquitination.
2024-11-20 | GSE275118 | GEO
Project description:An E2 ubiquitin conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function
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Project description:Histone H2B^3-32, H2B K->G, H2B^3-37, and H2B^30-37 mutations
| PRJNA94007 | ENA
Project description:Histone H2B was mutated to give H2B^3-32, H2B K->G, H2B^3-37, and H2B^30-37. Total RNA from three replicate cultures of wild-type and mutant was isolated and the expression profiles were determined using Affymetrix arrays. Comparisons between the sample groups allow the identification of genes regulated by H2B HBR domain. This SuperSeries is composed of the SubSeries listed below.
2006-04-08 | GSE3806 | GEO
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:Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism governs the loss-of-function oncohistone remains unclear. We generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B, disrupted cell divisions, and caused animal sterility. By performing genetic suppressor screens, we uncovered that mutations defective in the histone H3-H4 chaperone UNC-85 restored H2B 3KO fertility by decreasing chromatin H3-H4 levels. RNA interference of other H3-H4 chaperones or H3 or H4 histones also rescued H2B 3KO sterility. We showed that blocking H3-H4 chaperones recovered cell division in C. elegans carrying the oncohistone H2BE74K mutation that distorts the H2B-H4 interface and induces nucleosome instability. Our results indicate that reducing chromatin H3-H4 rescues the dysfunctional H2B in vivo and suggest that inhibiting H3-H4 chaperones may provide an effective therapeutic strategy for treating cancers resulting from loss-of-function H2B oncohistone.
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Project description:The chaperone FACT and H2B ubiquitination maintain S. pombe genome architecture through genic and subtelomeric functions
| PRJNA510892 | ENA
Project description:Chromatin landscapes are disrupted during DNA replication and need to be restored faithfully to maintain appropriate gene expression, including post-translational modifications (PTMs) of newly deposited histones. Whether histones H2A-H2B are accurately recycled during DNA replication and the behaviour of their associated marks during and post replication is unknown. Here we comprehensively map key modifications on H2A-H2B including H2A.Z during DNA replication. We show that H2AK119ub, H2BK120ub, and H2A.Z are recycled quantitatively and accurately during DNA replication in a symmetrical manner. Recycling occurs independently from H3-H4 chaperone pathways apart from a minor role for Polymerase alpha. H2A-H2B modifications are restored rapidly post replication and are important for timely and accurate restoration of H3-H4 marks, such as H3K27me3. This work uncovers H3-H4 and H2A-H2B crosstalk in epigenome propagation across DNA replication and suggests a model where rapid short-term memory of recycled H2A-H2B marks facilitates reestablishment of slow, long-term memory chromatin states.
2023-02-06 | GSE222928 | GEO
Project description:Nucleosome assembly in vivo requires assembly factors, such as histone chaperones, to bind to histones and mediate their deposition onto DNA. In yeast, the essential histone chaperone FACT (FAcilitates Chromatin Transcription) functions in nucleosome assembly and H2A-H2B deposition during transcription elongation and DNA replication. Recent studies have identified candidate histone residues that mediate FACT binding to histones, but it is not known which histone residues are important for FACT to deposit histones onto DNA during nucleosome assembly. In this study, we report that the histone H2B repression (HBR) domain within the H2B N-terminal tail is important for histone deposition by FACT. Deletion of the HBR domain causes significant defects in histone occupancy in the yeast genome, particularly at HBR-repressed genes, and a pronounced increase in H2A-H2B dimers that remain bound to FACT in vivo. Moreover, the HBR domain is required for purified FACT to efficiently assemble recombinant nucleosomes in vitro. We propose that the interaction between the highly basic HBR domain and DNA plays an important role in stabilizing the nascent nucleosome during the process of histone H2A-H2B deposition by FACT. 6 samples, 2 inputs and 4 ChIP samples for histone H2B (2 for wild-type and 2 for an H2B â30-37 mutant)
2016-08-10 | E-GEOD-80831 | biostudies-arrayexpress