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Loss of CREBBP results in H3K27Ac loss at enhancers and gene expression repression in lymphoma cells

ABSTRACT: Loss of CREBBP results in H3K27Ac loss at enhancers and gene expression repression in lymphoma cells

PROVIDER: PRJNA316703 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3304980.fastq.gz	Fastqsanger.gz
	SRR3304990.fastq.gz	Fastqsanger.gz
	SRR3305000.fastq.gz	Fastqsanger.gz
	SRR3305010.fastq.gz	Fastqsanger.gz
	SRR3309360_1.fastq.gz	Fastqsanger.gz

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Loss of CREBBP results in H3K27ac loss at enhancers in lymphoma cells

Project description:KD of CREBBP at lymphoma cell line, MD901, results in reduced H3K27ac enrichment at a subset of promoters and enhancers.

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Loss of CREBBP results in H3K27ac loss at enhancers in mouse lymphoma cells

Project description:KD of Crebbp at mouse cells results in reduced H3K27ac enrichment at a subset of promoters and enhancers.

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Loss of CREBBP results in gene expression repression in lymphoma cells

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Loss of CREBBP results in gene expression represssion in mouse lymphoma cells

Project description:KD of Crebbp at mouse cells results in reduced expression

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

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.

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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

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Loss of CREBBP results in H3K27Ac loss at enhancers and gene expression repression in lymphoma cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-10-13 | GSE79686 | GEO

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors

Project description:Loss of function mutations of the histone acetyltransferase CREBBP have recently been described at high frequencies across a spectrum of lymphoid malignancies. The multiple effects of this epigenetic regulator on developmental and homeostatic processes have been extensively studied, however, exactly how CREBBP functions as a tumour suppressor remains unclear. Here we use a murine model to demonstrate that loss of Crebbp in haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphoproliferative disorders (LPD). We identify a pre-malignant (PM) B220+ Mac1+ stem cell which ultimately transforms to LPD and shed light on the mechanisms of malignant evolution by comparing lymphoid progenitors, pre-malignant and malignant cells at the clonal, transcriptional, epigenetic and genetic levels. We demonstrate that loss of Crebbp in HSPCs facilitates the development of lymphoid malignancies by generating a hyperproliferative population of lymphoid progenitors with an altered response to DNA-damage and enhanced self-renewal properties. Global genomic profiling revealed that epigenetic alterations observed in lymphoid progenitors correlated highly with transcriptional changes observed in frank LPD. Taken together, these findings define the tumour suppressor functions of Crebbp and shed light on the cellular origins and subsequent evolution of lymphoid malignancies.

2017-12-13 | GSE92344 | GEO

Expression data from WT, Crebbp+/- and Ep300+/- bone marrow stroma

Project description:We found that the bone marrow microenvironment of Crebbp+/- mice was unable to properly maintain the immature stem - and progenitor pools. Instead, it stimulates myeloid differentiation that progresses into a myeloproliferative-like disease. Since CREBBP is a transcriptional co-activator, we used gene expression analysis to globally assess functional deficiencies in Crebbp+/- bone marrow stroma cells at a molecular level. Ep300 encodes a protein which is highly similar in structure and function to CREBBP; nevertheless, Ep300+/- mice suffer neither excessive myeloid differentiation nor loss of HSCs. Therefore, to identify expression changes specifically related to Crebbp heterozygosity, we focused on genes that showed significant differences in expression levels between Crebbp+/- and wild-type bone marrow stroma but no difference between Ep300+/- and wild-type. Bone marrow stroma was established from wild-type, Crebbp+/- and Ep300+/- mice that were 3-4 months old for RNA extraction and hybridization on Affymetrix microarrays. There are 4 biological replicates for each genotype used.

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