Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A histone H3.3K36M mutation in mice causes an imbalance of histone modifications and defects in chondrocyte differentiation.

ABSTRACT: Histone lysine-to-methionine (K-to-M) mutations have been identified as driver mutations in human cancers. Interestingly, these 'oncohistone' mutations inhibit the activity of histone methyltransferases. Therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we generated a genetically engineered mouse line in which an H3.3K36M mutation could be induced in the endogenous H3f3b gene. Since H3.3K36M has been identified as a causative mutation of human chondroblastoma, we induced this mutation in the chondrocyte lineage in mouse embryonic limbs. We found that H3.3K36M causes a global reduction in H3K36me2 and defects in chondrocyte differentiation. Importantly, the reduction of H3K36me2 was accompanied by a collapse of normal H3K27me3 distribution. Furthermore, the changes in H3K27me3, especially the loss of H3K27me3 at gene regulatory elements, were associated with the mis-regulated expression of a set of genes important for limb development, including HoxA cluster genes. Thus, through the in vivo induction of the H3.3K36M mutation, we reveal the importance of maintaining the balance between H3K36me2 and H3K27me3 during chondrocyte differentiation and limb development.

SUBMITTER: Abe S

PROVIDER: S-EPMC8510613 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation

Project description:Histone lysine-to-methionine (K-to-M) mutations have been identified as driver mutations in human cancers. Interestingly, these ‘oncohistone’ mutations inhibit the activity of histone methyltransferases. Therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we generated a genetically engineered mouse line in which an H3.3K36M mutation could be induced in the endogenous H3f3b gene. Since H3.3K36M has been identified as a causative mutation of human chondroblastoma, we induced this mutation in the chondrocyte lineage in mouse embryonic limbs. We found that H3.3K36M causes a global reduction in H3K36me2 and defects in chondrocyte differentiation. Importantly, the reduction of H3K36me2 was accompanied by a collapse of normal H3K27me3 distribution. Furthermore, the changes in H3K27me3, especially the loss of H3K27me3 at gene regulatory elements, were associated with the mis-regulated expression of a set of genes important for limb development, including HoxA cluster genes. Thus, through the in vivo induction of the H3.3K36M mutation, we reveal the importance of maintaining the balance between H3K36me2 and H3K27me3 during chondrocyte differentiation and limb development.

2020-11-01 | GSE150353 | GEO

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [RNA-seq]

Project description:Histone lysine-to-methionine (K-to-M) mutations have been identified as driver mutations in human cancers. Interestingly, these ‘oncohistone’ mutations inhibit the activity of histone methyltransferases, and, therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we created a conditional knock-in mouse line in which a H3.3K36M mutation can be induced in the endogenous H3.3 gene. Since the H3.3K36M mutation has been identified as a causative mutation of human chondroblastoma, we induced this mutation in the chondrocyte lineage in mouse embryonic limbs. We found that H3.3K36M causes global reduction of H3K36me2 and defects in chondrocyte differentiation. Importantly, the reduction of H3K36me2 was accompanied by a collapse of normal H3K27me3 distribution. Furthermore, the changes in H3K27me3, especially the loss of H3K27me3 at gene regulatory elements, were associated with misregulated expression of a set of genes important for limb development including HoxA cluster genes. Thus, taking advantage of the in vivo induction of H3.3K36M mutation, we reveal the importance of a counterbalance between H3K36me2 and H3K27me3 for chondrocyte differentiation and limb development.

2020-11-01 | GSE150352 | GEO

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [ChIP-seq]

Project description:Histone lysine-to-methionine (K-to-M) mutations have been identified as driver mutations in human cancers. Interestingly, these ‘oncohistone’ mutations inhibit the activity of histone methyltransferases, and, therefore, they can potentially be used as versatile tools to investigate the roles of histone modifications. In this study, we created a conditional knock-in mouse line in which a H3.3K36M mutation can be induced in the endogenous H3.3 gene. Since the H3.3K36M mutation has been identified as a causative mutation of human chondroblastoma, we induced this mutation in the chondrocyte lineage in mouse embryonic limbs. We found that H3.3K36M causes global reduction of H3K36me2 and defects in chondrocyte differentiation. Importantly, the reduction of H3K36me2 was accompanied by a collapse of normal H3K27me3 distribution. Furthermore, the changes in H3K27me3, especially the loss of H3K27me3 at gene regulatory elements, were associated with misregulated expression of a set of genes important for limb development including HoxA cluster genes. Thus, taking advantage of the in vivo induction of H3.3K36M mutation, we reveal the importance of a counterbalance between H3K36me2 and H3K27me3 for chondrocyte differentiation and limb development.

2020-11-01 | GSE150351 | GEO

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation

Project description:A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation

| PRJNA631838 | ENA

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [ChIP-seq]

Project description:A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [ChIP-seq]

| PRJNA631842 | ENA

A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [RNA-seq]

Project description:A histone H3.3K36M mutation in mice causes imbalance of histone modifications and defects in chondrocyte differentiation [RNA-seq]

| PRJNA631841 | ENA

Nanophthalmos-Associated MYRF Gene Mutation Causes Ciliary Zonule Defects in Mice.

Project description:PurposePatients with nanophthalmos who undergo intraocular surgery often present with abnormal ciliary zonules. In a previous study, we reported mutation in MYRF that is implicated in the pathogenesis of nanophthalmos. The aim of this study was to model the mutation in mice to explore the role of MYRF on zonule structure and its major molecular composition, including FBN1 and FBN2.MethodsHuman MYRF nanophthalmos frameshift mutation was generated in mouse using the CRISPR-Cas9 system. PCR and Sanger sequencing were used for genotype analysis of the mice model. Anterior chamber depth (ACD) was measured using hematoxylin and eosin-stained histology samples. Morphologic analysis of ciliary zonules was carried out using silver staining and immunofluorescence. Transcript and protein expression levels of MYRF, FBN1, and FBN2 in ciliary bodies were quantified using quantitative real-time PCR (qRT-PCR) and Western blot.ResultsA nanophthalmos frameshift mutation (c.789delC, p.N264fs) of MYRF in mice showed ocular phenotypes similar to those reported in patients with nanophthalmos. ACD was reduced in MYRF mutant mice (MYRFmut/+) compared with that in littermate control mice (MYRF+/+). In addition, the morphology of ciliary zonules showed reduced zonular fiber density and detectable structural dehiscence of zonular fibers. Furthermore, qRT-PCR analysis and Western blot showed a significant decrease in mRNA expression levels of MYRF, FBN1, and FBN2 in MYRFmut/+ mice.ConclusionsChanges in the structure and major molecular composition of ciliary zonules accompanied with shallowing anterior chamber were detected in MYRFmut/+ mice. Therefore, MYRF mutant mice strain is a useful model for exploring pathogenesis of zonulopathy, which is almost elusive for basic researches due to lack of appropriate animal models.

| S-EPMC7937999 | biostudies-literature

Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe.

Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in 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, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication 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 have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

| S-EPMC5515577 | biostudies-literature

Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice.

Project description:In humans, hereditary inactivation of either p22(phox) or gp91(phox) leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22(phox) and gp91(phox) proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22(phox) deficiency. Characterization of nmf333 mice revealed that deletion of p22(phox) inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22(phox)-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22(phox) represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22(phox) expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.

| S-EPMC2248803 | biostudies-literature

A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice.

Project description:The hush puppy mouse mutant has been shown previously to have skull and outer, middle, and inner ear defects, and an increase in hearing threshold. The fibroblast growth factor receptor 1 (Fgfr1) gene is located in the region of chromosome 8 containing the mutation. Sequencing of the gene in hush puppy heterozygotes revealed a missense mutation in the kinase domain of the protein (W691R). Homozygotes were found to die during development, at approximately embryonic day 8.5, and displayed a phenotype similar to null mutants. Reverse transcription PCR indicated a decrease in Fgfr1 transcript in heterozygotes and homozygotes. Generation of a construct containing the mutation allowed the function of the mutated receptor to be studied. Immunocytochemistry showed that the mutant receptor protein was present at the cell membrane, suggesting normal expression and trafficking. Measurements of changes in intracellular calcium concentration showed that the mutated receptor could not activate the IP(3) pathway, in contrast to the wild-type receptor, nor could it initiate activation of the Ras/MAP kinase pathway. Thus, the hush puppy mutation in fibroblast growth factor receptor 1 appears to cause a loss of receptor function. The mutant protein appears to have a dominant negative effect, which could be due to it dimerising with the wild-type protein and inhibiting its activity, thus further reducing the levels of functional protein. A dominant modifier, Mhspy, which reduces the effect of the hush puppy mutation on pinna and stapes development, has been mapped to the distal end of chromosome 7 and may show imprinting.

| S-EPMC3099004 | biostudies-literature

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