Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

ABSTRACT: 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.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE185582 | GEO | 2022/04/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

Project description:Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

| PRJNA769715 | ENA

An E2 ubiquitin conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function

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

Recycling of H2A-H2B provides short-term memory of chromatin states [ChOR-Seq]

Project description:Chromatin landscapes are disrupted during DNA replication and must be restored faithfully to maintain genome regulation and cell identity. The H3-H4 modification landscape is restored by parental histone recycling and post-replication modification of new histone H3-H4. How DNA replication impact on histone H2A-H2B is unknown. Here, we track H2A-H2B modifications and H2A.Z during DNA replication and across the cell cycle using quantitative genomics. We show that H2AK119ub, H2BK120ub, and H2A.Z are recycled quantitatively and accurately during DNA replication. H2A-H2B are recycled symmetrically to daughter strands largely independent of known H3-H4 recycling pathways. Post-replication, H2A-H2B modifications are rapidly restored, and the rapid wave of H2AK119ub supports accurate restoration of H3K27me3. This work reveals epigenetic transmission of H2A-H2B modification during DNA replication and identifies H3-H4 and H2A-H2B crosstalk in epigenome propagation. We propose that rapid short-term memory of recycled H2A-H2B modifications facilitates reestablishment of slow, long-term chromatin state memory.

2023-02-06 | GSE204981 | GEO

Recycling of H2A-H2B provides short-term memory of chromatin states [ChIP-Seq]

2023-02-06 | GSE204974 | GEO

Recycling of H2A-H2B provides short-term memory of chromatin states [SCAR-Seq]

2023-02-06 | GSE204984 | GEO

LC-MS/MS identification of histone Kbz sites in yeast

Project description:Identification of 29 Kbz sites on yeast H3, H4, H2A, H2A.Z, and H2B by LC-MS/MS.

2022-05-20 | PXD030070 | Pride

Recycling of Histones H2A-H2B provides short-term memory of chromatin states [SCAR-seq II]

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

A role of RPA in replication coupled nucleosome assembly

Project description:Chromatin replication requires tight coordination of nucleosome assembly machinery with DNA replication machinery. While significant progress has been made in characterizing histone chaperones in this process, the mechanism of whereby nucleosome assembly couples with DNA replication remains largely unknown. Here we show that replication protein A (RPA), a single-stranded DNA (ssDNA) binding protein that is essential for DNA replication provides a binding platform for H3-H4 deposition by histone chaperons and is required for nucleosome formation on nascent chromatin. RPA binds free histone H3-H4 but not nucleosomal histones, and a RPA coated ssDNA stimulates assembly of H3-H4 onto double strand DNA in vitro. RPA mutant with reduced H3-H4 binding exhibits synthetic genetic interaction with mutations at key factors involved in replication-coupled (RC) nucleosome assembly, and are defective in assembly of replicating DNA into nucleosomes in cells. These results reveal a novel function for RPA in nucleosome assembly and a mechanism whereby nucleosome assembly is coordinated with DNA replication.

2017-01-27 | GSE83648 | GEO

Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.

2023-05-08 | PXD040835 | Pride

mRNA-seq analysis of Caenorhabditis elegans daf-18(ok480) and WT starved L1 larvae shortly after hatching

Project description:Whole L1 larvae were collected from GC1459 [naSi2 [pGC550 (mex-5p::mCherry::H2B::nos-2 3'UTR +unc-119(+))] II; unc-119(ed3) III ?; daf-18(ok480) IV] and GC1171 [naSi2 [pGC550 (mex-5p::mCherry::H2B::nos-2 3'UTR +unc-119(+))] II; unc-119(ed3) III] strains up to two hours after hatching without food.

2021-06-21 | GSE151299 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data