Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts

ABSTRACT: The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. We investigated individual functions of CBP and p300 using a silencing strategy, followed by RNA-sequencing, and pathway enrichment analysis. We have selected stress-related pathways for a further in-depth investigation of individual functions of CBP and p300 in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236122 | GEO | 2023/07/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcription profiling of mouse embryonic fibroblasts C57Bl/6x129/Sv F2 e14.5 embryos vs controls grown in hypoxic or normoxic conditions

Project description:The CH1 protein interaction domain of the transcriptional coactivators p300 and CBP is thought to interact with HIF-1alpha and this interaction is thought to be critical to the expression of HIF-1alpha target genes in response to hypoxia. To test the requirement of the CH1 domain for gene expression in response to hypoxia, rimary mouse embryonic fibroblasts (MEFs) were generated from C57Bl/6x129/Sv F2 e14.5 embryos that contain a deletion in the CH1 domain of three of four alleles of CBP and p300. The remaining allele of p300 or CBP was a conditional knock out allele. Control MEFs with only a single conditional knockout allele of p300 or CBP were also generated. At passage 3 MEFs were infected with Cre Adenovirus and grown until they had expanded at least 100 fold. Subconfluent MEFs were treated with 21% oxygen (normoxia) or 0.1% oxygen (hypoxia) with 5% carbon dioxide at 37 C in a humid chamber for 6hrs. At the start of treatment, medium was removed and replaced with medium (DMEM+10% FBS+pen-strep+ l-glu) that had been preequilibrated overnight in normoxia or hypoxia as appropriate. Immediately after treatment, cells were lysed in Trizol for RNA extraction. 12 samples; 4 genotypes [CBP+/flox (flox1), p300 +/flox (flox2), CBP CH1/flox;p300 CH1/CH1 (triCH1flox1),CBP CH1/CH1;p300 CH1/flox (triCH1flox2)] , 2 treatments (normoxia and hypoxia).

2007-12-15 | E-GEOD-3196 | biostudies-arrayexpress

Transcription profiling of mouse embryonic fibroblasts from embryos with ?CH1 mutation in p300 and/or CBP atreated with hypoxia or dipyridyl (a hypoxia mimetic) and trichostatin A (a histone deacetylase inhibitor) reveals two transactivation mechanisms are responsible for the bulk of HIF-1alpha-responsive gene expression

Project description:The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1? and HIF-2? binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (?CH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of ~35-50% of global HIF-1?-responsive gene expression, whereas another HIF-transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSAS) accounts for ~70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription. Experiment Overall Design: Three separate affymetrix experiments using mouse embryonic fibroblasts derived from embryos bearing the ?CH1 mutation in p300 and/or CBP and treated with hypoxia or combinations of dipyridyl (a hypoxia mimetic) and trichostatin A (a histone deacetylase inhibitor) are described (GSE3195, GSE3196 and GSE3296). Samples are not directly comparable between experiments because of differences in experiment design and Affymetrix chips used.

2008-06-12 | E-GEOD-3318 | biostudies-arrayexpress

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [HepG2]

Project description:Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, amyloid-β aggregation reduction and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

2020-12-07 | GSE156830 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [ChIP-seq]

2020-12-07 | GSE148328 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [Mus musculus]

2020-12-07 | GSE131613 | GEO

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [C. elegans]

2020-12-07 | GSE131611 | GEO

Transcription profiling of primary mouse embryonic fibroblasts (MEFs) from C57Bl/6x129/Sv F2 e14.5 embryos that contain a deletion in the CH1 domain of three of four alleles of CBP and p300

Project description:The CH1 protein interaction domain of the transcriptional coactivators p300 and CBP is thought to interact with HIF-1alpha and this interaction is thought to be critical to the expression of HIF-1alpha target genes in response to hypoxia. Trichostatin A (TSA), an inhibitor of histone deacetylases, has been reported to repress the expression of HIF-1alpha target genes. To test the requirement of the CH1 domain and TSA for gene expression in response to dipyridyl (a hypoxia mimetic), primary mouse embryonic fibroblasts (MEFs) were generated from C57Bl/6x129/Sv F2 e14.5 embryos that contain a deletion in the CH1 domain of three of four alleles of CBP and p300. The remaining allele of p300 or CBP was a conditional knock out allele. Control MEFs with only a single conditional knockout allele of p300 or CBP were also generated. At passage 3 MEFs were infected with Cre Adenovirus and grown until they had expanded at least 100 fold. Subconfluent MEFs were treated with ethanol vehicle or 100ng/ml TSA with 5% carbon dioxide at 37 C in a humid chamber for 30 min., followed by ethanol vehicle or 100 umdipyridyl (DP) for an additional 3hrs. Immediately after treatment, cells were lysed in Trizol for RNA extraction.

2007-07-07 | E-GEOD-3296 | biostudies-arrayexpress

Gene expression in hypoxic MEFs having only p300 and CBP with deleted CH1 domains

2005-10-24 | GSE3196 | GEO

Expression data from wild type and CBP/p300 null MEFs +/- 3hr treatment with 100uM dipyridyl (DP)

Project description:Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, Crebbp (CBP) and Ep300 (p300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 remains largely uncertain. We investigated this relationship by comparing genomic CBP recruitment with gene expression in wild type and CBP/p300 double-knockout fibroblasts. ChIP-seq revealed nearby CBP recruitment for 20 percent of constitutively expressed genes, but surprisingly, three-quarters of these were unaffected or slightly activated by CBP/p300 deletion. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak within two kilobases of the enhancer-like element provided better predictive value, with CBP/p300 deletion attenuating expression of 40 percent of such EPU assigned constitutively expressed genes. We next examined signaling-responsive (Hypoxia Inducible Factor) gene expression and CBP recruitment, and found that 97 percent of inducible genes were within 50 kilobases of an inducible CBP peak, and 70 percent of these required CBP/p300 for full inducible expression. Unexpectedly however, most inducible CBP peaks occurred near signal-nonresponsive genes. 12 samples, 3 each wild type and CBP/p300 null treated for 3hrs with 100uM dipyridyl orethanol vehicle.

2014-09-29 | E-GEOD-54452 | biostudies-arrayexpress

CREBBP (CBP) ChIP-seq in wild type and CBP null MEFs +/- dipyridyl

Project description:Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, Crebbp (CBP) and Ep300 (p300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 remains largely uncertain. We investigated this relationship by comparing genomic CBP recruitment with gene expression in wild type and CBP/p300 double-knockout fibroblasts. ChIP-seq revealed nearby CBP recruitment for 20 percent of constitutively expressed genes, but surprisingly, three-quarters of these were unaffected or slightly activated by CBP/p300 deletion. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak within two kilobases of the enhancer-like element provided better predictive value, with CBP/p300 deletion attenuating expression of 40 percent of such EPU assigned constitutively expressed genes. We next examined signaling-responsive (Hypoxia Inducible Factor) gene expression and CBP recruitment, and found that 97 percent of inducible genes were within 50 kilobases of an inducible CBP peak, and 70 percent of these required CBP/p300 for full inducible expression. Unexpectedly however, most inducible CBP peaks occurred near signal-nonresponsive genes. eight samples total; Two wild type and two CBP null primary mouse embryonic fibroblast (MEF) lines, each treated with 100uM 2,2-dipyridyl or ethanol vehicle for 2 hours

2014-09-29 | E-GEOD-54453 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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