Investigating the role of Foxp1 in murine A20 lymphoma cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139536 | GEO | 2020/04/03
REPOSITORIES: GEO
Similar Datasets
Project description:Investigating the role of Foxp1 in murine A20 lymphoma cells
| PRJNA580222 | ENA
Project description:The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through immunoglobulin heavy chain (IGH) locus-related chromosomal translocations leading to dysregulated expression of FOXP1. Translocations of FOXP1 with non-IG gene sequences have been also reported, but the molecular consequences of such aberrations remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas without underlying t(3p13/FOXP1). We found that non-IG rearrangements are usually acquired during evolution of lymphoma and constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). Intriguingly, these rearrangements do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms, as shown by QRT-PCR and Western blot analysis. In contrast, cases with t(3;14)(p13;q32)/IGH-FOXP1 overexpress the full-length FOXP1. Collectively, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. The primary t(3;14)(p13;q32)/IGH-FOXP1 produces the full-length protein with potent oncogenic activity, whereas the secondary non-IG 17 rearrangements of FOXP1 generate N-truncated FOXP1 isoforms, likely driving progression of disease. Using molecular cytogenetics and molecular biology studies (including RNA-seq), we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas without underlying t(3p13/FOXP1).
2013-09-04 | E-GEOD-50514 | biostudies-arrayexpress
Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). Single-cell sequencing reveals “pre-lymphoma” transcription signatures in lymphocytes of HA20 patients.
2023-07-12 | E-MTAB-12485 | biostudies-arrayexpress
Project description:The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through immunoglobulin heavy chain (IGH) locus-related chromosomal translocations leading to dysregulated expression of FOXP1. Translocations of FOXP1 with non-IG gene sequences have been also reported, but the molecular consequences of such aberrations remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas without underlying t(3p13/FOXP1). We found that non-IG rearrangements are usually acquired during evolution of lymphoma and constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). Intriguingly, these rearrangements do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms, as shown by QRT-PCR and Western blot analysis. In contrast, cases with t(3;14)(p13;q32)/IGH-FOXP1 overexpress the full-length FOXP1. Collectively, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. The primary t(3;14)(p13;q32)/IGH-FOXP1 produces the full-length protein with potent oncogenic activity, whereas the secondary non-IG 17 rearrangements of FOXP1 generate N-truncated FOXP1 isoforms, likely driving progression of disease.
2013-09-04 | GSE50514 | GEO
Project description:ChIP-Sequencing of 4 diffuse large B-cell lymphoma cell lines expressing different amounts of FOXP1 was performed in order to identify target genes bound by the transcription factor FOXP1.
2015-11-30 | E-MTAB-3741 | biostudies-arrayexpress
Project description:Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of CRISPR dCas9-based activation systems. To counter this, we created an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). To evaluate the specificity of our TETact system, we conducted RNA-seq on A20 cells containing the TETact-v3 system targeting the CD4 promoter, along with non-targeting control TETact-v3 cells as well as wildtype A20. A20 is a BALB/C B cell lymphoma cell line that does not normally express CD4. Non-transduced A20 showed a very similar gene expression profile with the control TETact-v3 cells. Importantly, comparing of TETact-v3 cells targeting CD4 promoter to with cells expressing non-targeting sgRNA revealed CD4 as the sole significantly upregulated gene. Expression of the other genes in the CD4-targeting samples correlated strongly with the control sample. Together these experiments reveal the exquisite specificity of the TETact system.
2022-09-07 | GSE203162 | GEO
Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 33 HA20 patients, we show that heterozygous TNFAIP3 loss skews immune repertoires towards lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas.
2023-07-28 | E-MTAB-12491 | biostudies-arrayexpress
Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
2015-12-01 | GSE64586 | GEO
Project description:Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A knock-in cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was adressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeoloid cells did not give rise to enhanced NF-κB signaling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
2019-07-10 | GSE116780 | GEO
Project description:Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of CRISPR dCas9-based activation systems. To counter this, we created an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). To evaluate the specificity of our TETact system, we conducted RNA-seq on A20 cells containing the TETact-v3 system targeting the CD4 promoter, along with non-targeting control TETact-v3 cells as well as wildtype A20. A20 is a BALB/C B cell lymphoma cell line that does not normally express CD4. Non-transduced A20 showed a very similar gene expression profile with the control TETact-v3 cells. Importantly, comparing of TETact-v3 cells targeting CD4 promoter to with cells expressing non-targeting sgRNA revealed CD4 as the sole significantly upregulated gene. Expression of the other genes in the CD4-targeting samples correlated strongly with the control sample. Together these experiments reveal the exquisite specificity of the TETact system.
2022-09-07 | GSE211754 | GEO