Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

H3K27Ac mapping in isogenic CREBBP-WT, CREBBP-KO and EP300-KO SUDHL4 cell lines

ABSTRACT: Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132365 | GEO | 2020/02/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptional profiling of murine germinal center (GC) B cells from GC-specific conditional Crebbp and Ep300 knock-out mice

Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.

2021-06-01 | GSE124192 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.

2020-06-18 | GSE152667 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

2020-06-18 | GSE152666 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

2020-06-18 | GSE152665 | GEO

Identification of CREBBP bound genes in germinal center B cells

Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from the germinal-center (GC). However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Using functional epigenomics and mouse genetics, here we define the program modulated by CREBBP in primary human GC B cells and show that CREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouse perturbs the expression of a limited set of genes involved in the regulation of signal transduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) and terminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cells exhibit proliferative advantage and show impaired plasma cell differentiation. While GC-specific loss of Crebbp was not sufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignancies recapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights into the mechanisms and targets by which loss of CREBBP contributes to lymphomagenesis.

2017-01-11 | GSE89688 | GEO

Transcriptomic profile of germinal center B cells from conditional GC-specific (Cg1-Cre) Crebbp-HET, Kmt2d-HET, and compound Crebbp-HET/Kmt2d-HET mice, with littermate controls

Project description:Inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B-cell lymphoma and co-occur in 40-60% of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be co-selected. Here we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergize in vivo to promote the expansion of abnormal GCs, a common pre-neoplastic event. These enzymes form a biochemical complex on selected enhancers/super-enhancers that are critical for the delivery of signals in the GC light-zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCLs. Moreover, we find that CREBBP directly acetylates KMT2D in GC-derived B cells. Accordingly, inactivation of CREBBP by FL/DLBCL-associated truncating and/or missense mutations abrogates its ability to catalyze KMT2D acetylation. Importantly, genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation leads to reduced levels of H3K4me1, supporting a role for acetylation in modulating KMT2D activity. These data identify a direct biochemical and functional interaction between CREBBP and KMT2D, with implications for their role as tumor suppressors in FL/DLBCL and for the development of combinatorial therapies targeting enhancer defects induced by their loss.

2023-02-28 | GSE220255 | GEO

Gene expression profile analysis of germinal center B cells from conditional Crebbp knockout mice and littermate controls

Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from thegerminal-center (GC). However, the role of CREBBP inactivation in lymphomagenesisremains unclear. Using functional epigenomics and mouse genetics, here we definethe program modulated by CREBBP in primary human GC B cells and show thatCREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouseperturbs the expression of a limited set of genes involved in the regulation of signaltransduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) andterminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cellsexhibit proliferative advantage and show impaired plasma cell differentiation. WhileGC-specific loss of Crebbp was not sufficient to initiate malignant transformation,compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignanciesrecapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights intothe mechanisms and targes by which loss of CREBBP contributes to lymphomagenesis.

2017-01-11 | GSE88799 | GEO

Transcriptome profiling (RNA-seq) of CREBBP+/+ and CREBBP+/- clones of U2932 DLBCL cell line

Project description:Purpose: Diffuse large B cell lymphomas (DLBCL) frequently harbor mutations in the histone acetyltransferase CREBBP, however their functional contribution to lymphomagenesis remains largely unknown. This study aims at elucidating and characterizing the molecular pathways affected by mutations in CREBBP. Methods: U2932, a DLBCL cell line that has wild type expression of CREBBP was manipulated by CRISPR-Cas9 strategy to mutate one allele of CREBBP and examine the pathways affected. RNA was isolated using the NucleoSping RNA Kit (Macherey-Nagel) from five wild type (CREBBP+/+) and five heterozygous clones (CREBBP+/-). RNA quality was assessed by Bioanalyzer 2100 followed by library preparation using the TruSeq RNA Sample Prep Kit v4 (Illumina). Sequencing was subsequently performed on the Illumina HiSeq 2500 instrument. RNA-seq reads were quality-checked with fastqc, which computes various quality metrics for the raw reads. RNA-seq reads were mapped to the GRCh38 reference human genome using STAR and reads were counted according to Ensembl gene annotation using the featureCounts function in the Rsubread Bioconductor package. Statistical analysis of differential expression was conducted with the DESeq2 package.

2016-11-16 | GSE89879 | GEO

H3K27Ac mapping in isogenic CREBBP-WT, CREBBP-KO and EP300-KO SUDHL4 cell lines

Project description:H3K27Ac mapping in isogenic CREBBP-WT, CREBBP-KO and EP300-KO SUDHL4 cell lines

| PRJNA547757 | ENA

Targeting CREBBP/EP300 in cancer

Project description:Antiprolifereative effects of CREBBP/EP300 inhibitors were tested in human leukemia and lymphoma cell lines and the molecular mechanisms responsible for such effects were explored.

2018-06-12 | GSE77295 | GEO

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