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
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ABSTRACT:
PROVIDER: PRJNA909299 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23049285_1.fastq.gz | Fastqsanger.gz | |||
| SRR23049285_2.fastq.gz | Fastqsanger.gz | |||
| SRR23049286_1.fastq.gz | Fastqsanger.gz | |||
| SRR23049286_2.fastq.gz | Fastqsanger.gz | |||
| SRR23049287_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Gene expression profiling of murine eGFP+ relfl/flCg1-Cre and eGFP− Cg1-Cre splenic germinal center B cells identifies genes regulated by the transcription factor c-REL in germinal center B cells. Germinal center B cells from 12-week old relfl/flCg1-Cre and Cg1-Cre littermate mice immunized with sheep red blood cells (SRBC) were isolated at day 7 after immunization by flow cytometric sorting from splenic mononuclear cells. RNA was isolated. Following a cDNA amplification step, labeled cRNA was hybridized to microarrays and genes specifically expressed in eGFP+ relfl/flCg1-Cre and eGFP− Cg1-Cre samples were identified by supervised analysis.
2014-07-15 | E-GEOD-58839 | biostudies-arrayexpress
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
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Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-02-19 | GSE224782 | GEO
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-03-05 | GSE260811 | GEO
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-02-19 | GSE224781 | GEO
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-02-19 | GSE224512 | GEO
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-02-19 | GSE224465 | GEO
Project description:Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
2024-03-05 | GSE260810 | GEO
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