Chromatin binding of MEF2B and SMARCA4 in normal human germinal center B cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA982708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24894046_1.fastq.gz | Fastqsanger.gz | |||
| SRR24894046_2.fastq.gz | Fastqsanger.gz | |||
| SRR24894047_1.fastq.gz | Fastqsanger.gz | |||
| SRR24894047_2.fastq.gz | Fastqsanger.gz | |||
| SRR24894048_1.fastq.gz | Fastqsanger.gz |
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Project description:The MEF2B transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its N-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of C-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at S324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. These assorted mechanisms provide additional opportunities for the development of targeted therapeutic approaches.
2024-08-26 | PXD043998 | Pride
Project description:The MEF2B transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its N-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of C-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at S324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. These assorted mechanisms provide additional opportunities for the development of targeted therapeutic approaches.
2024-07-26 | GSE234656 | GEO
Project description:The MEF2B transcription factor is recurrently mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in normal and neoplastic GC development is unknown. Here we identify MEF2B transcriptional targets in GC, which indicate its control of cell proliferation, apoptosis, GC confinement and differentiation. Consistently, Mef2b deletion reduces GC formation in mice. The most common tumor-associated MEF2B mutant (MEF2BD83V) is hypomorphic, but escapes binding and negative regulation by Cabin1 and HDACs. Mef2bD83V expression leads to GC enlargement and GC-derived tumors in 25% of the animals. This phenotype becomes fully penetrant in combination with BCL2 de-regulation, an event commonly associated with MEF2B mutations in human lymphoma. These results identify MEF2B as a critical GC regulator, and as a dominant oncogene in lymphomagenesis.
2018-09-10 | GSE110676 | GEO
Project description:The MEF2B transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its N-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of C-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at S324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. These assorted mechanisms provide additional opportunities for the development of targeted therapeutic approaches.
2024-07-26 | GSE234657 | GEO
Project description:The MEF2B transcription factor is recurrently mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in normal and neoplastic GC development is unknown. Here we identify MEF2B transcriptional targets in GC, which indicate its control of cell proliferation, apoptosis, GC confinement and differentiation. Consistently, Mef2b deletion reduces GC formation in mice. The most common tumor-associated MEF2B mutant (MEF2BD83V) is hypomorphic, but escapes binding and negative regulation by Cabin1 and HDACs. Mef2bD83V expression leads to GC enlargement and GC-derived tumors in 25% of the animals. This phenotype becomes fully penetrant in combination with BCL2 de-regulation, an event commonly associated with MEF2B mutations in human lymphoma. These results identify MEF2B as a critical GC regulator, and as a dominant oncogene in lymphomagenesis.
2018-09-10 | GSE110682 | GEO
Project description:Germinal Center B cell transcriptional profiles in Mef2b mouse models
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Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.
2020-04-06 | PXD015524 | Pride
Project description:Myocyte enhancer factor 2B (MEF2B) is a transcription factor with somatic mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The recurrence of these mutations indicates that they may drive lymphoma development. However, inferring the mechanisms by which they may drive lymphoma development was complicated by our limited understanding of MEF2B’s normal functions. To expand our understanding of the cellular activities of wildtype (WT) and mutant MEF2B, I developed and addressed two hypotheses: (1) identifying genes regulated by WT MEF2B will allow identification of cellular phenotypes affected by MEF2B activity and (2) contrasting the DNA binding sites, effects on gene expression and effects on cellular phenotypes of mutant and WT MEF2B will help refine hypotheses about how MEF2B mutations may contribute to lymphoma development. To address these hypotheses, I first identified genome-wide WT MEF2B binding sites and transcriptome-wide gene expression changes mediated by WT MEF2B. Using these data I identified and validated novel MEF2B target genes. I found that target genes of MEF2B included the cancer genes MYC, TGFB1, CARD11, NDRG1, RHOB, BCL2 and JUN. Identification of target genes led to findings that WT MEF2B promotes expression of mesenchymal markers, promotes HEK293A cell migration, and inhibits DLBCL cell chemotaxis. I then investigated how K4E, Y69H and D83V mutations change MEF2B’s activity. I found that K4E, Y69H and D83V mutations decreased MEF2B DNA binding and decreased MEF2B’s capacity to promote gene expression in both HEK293A and DLBCL cells. These mutations also reduced MEF2B’s capacity to alter HEK293A and DLBCL cell movement. From these data, I hypothesize that MEF2B mutations may promote DLBCL and FL development by reducing expression of MEF2B target genes that would otherwise function to help confine germinal centre B-cells to germinal centres. Overall, my research demonstrates how observations from genome-scale data can be used to identify cellular effects of candidate driver mutations. Moreover, my work provides a unique resource for exploring the role of MEF2B in cell biology: I map for the first time the MEF2B ‘regulome’, demonstrating connections between a relatively understudied transcription factor and genes significant to oncogenesis. ChIP-seq was performed using a V5 antibody on cells expressing V5 tagged WT and mutant MEF2B. Two biological replicates were performed on WT, K4E, Y69H and D83V MEF2B-V5 cells.
2015-07-01 | E-GEOD-67450 | biostudies-arrayexpress
Project description:Myocyte enhancer factor 2B (MEF2B) is a transcription factor with somatic mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The recurrence of these mutations indicates that they may drive lymphoma development. However, inferring the mechanisms by which they may drive lymphoma development was complicated by our limited understanding of MEF2B’s normal functions. To expand our understanding of the cellular activities of wildtype (WT) and mutant MEF2B, I developed and addressed two hypotheses: (1) identifying genes regulated by WT MEF2B will allow identification of cellular phenotypes affected by MEF2B activity and (2) contrasting the DNA binding sites, effects on gene expression and effects on cellular phenotypes of mutant and WT MEF2B will help refine hypotheses about how MEF2B mutations may contribute to lymphoma development. To address these hypotheses, I first identified genome-wide WT MEF2B binding sites and transcriptome-wide gene expression changes mediated by WT MEF2B. Using these data I identified and validated novel MEF2B target genes. I found that target genes of MEF2B included the cancer genes MYC, TGFB1, CARD11, NDRG1, RHOB, BCL2 and JUN. Identification of target genes led to findings that WT MEF2B promotes expression of mesenchymal markers, promotes HEK293A cell migration, and inhibits DLBCL cell chemotaxis. I then investigated how K4E, Y69H and D83V mutations change MEF2B’s activity. I found that K4E, Y69H and D83V mutations decreased MEF2B DNA binding and decreased MEF2B’s capacity to promote gene expression in both HEK293A and DLBCL cells. These mutations also reduced MEF2B’s capacity to alter HEK293A and DLBCL cell movement. From these data, I hypothesize that MEF2B mutations may promote DLBCL and FL development by reducing expression of MEF2B target genes that would otherwise function to help confine germinal centre B-cells to germinal centres. Overall, my research demonstrates how observations from genome-scale data can be used to identify cellular effects of candidate driver mutations. Moreover, my work provides a unique resource for exploring the role of MEF2B in cell biology: I map for the first time the MEF2B ‘regulome’, demonstrating connections between a relatively understudied transcription factor and genes significant to oncogenesis.
2015-07-01 | GSE67450 | GEO