Investigating the role of Foxp1 in murine A20 lymphoma cells
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ABSTRACT:
PROVIDER: PRJNA580222 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10359756_1.fastq.gz | Fastqsanger.gz | |||
| SRR10359756_2.fastq.gz | Fastqsanger.gz | |||
| SRR10359757_1.fastq.gz | Fastqsanger.gz | |||
| SRR10359757_2.fastq.gz | Fastqsanger.gz | |||
| SRR10359758_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: to investigate the role of transcription factor Foxp1 in murine A20 lymphoma cells, which can be used as a model for human diffuse large B cell lymphoma Method: Exons 6 and 7 of Foxp1 were independently targeted using CRISPR/Cas9 editing, and 2 clones from each targeted exon (E6 and E7), showing depleted Foxp1 isoforms were isolated. Method: RNA sequencing was conducted on parental A20 cells and CRISPR clones, and differential gene expression was undertaken
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Project description:Expression of the forkhead transcription factor FOXP1 is essential for early B cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, being associated with poor prognosis. Here, by gene expression microarray [GSE51382] and quantitative RT-PCR analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation-sequencing (ChIP-seq), we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs but expression strongly decreases during plasma PC differentiation. Moreover, as compared to IgM+ MBCs, IgG+ MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant overexpression of FOXP1 might contribute to lymphomagenesis by blocking terminal B cell differentiation.
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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).
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2010-09-18 | GSE24203 | GEO
Project description:Genome wide transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection. Overexpression of the NF-kB inhibitory protein A20 improves recovery of liver function and mass following extended liver resection and severe liver ischemia reperfusion injury in mice. In this project, we explored effects of A20 using transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection. A20 or beta-galactosidase gene expression in the mouse liver was achieved by penile vein injection of 1x109 pfu of rAd. in 100uL of normal saline, which results in optimal transgene expression 5 days after injection in 30% to 40% of hepatocytes (Longo et al, 2005). Extended (78%) LR, consisting of resection of the lateral, medial, left, and right lobes, was performed 5 days following rAd. administration in 8-week old BALB/c mice weighing 25 to 30 grams (Taconic, Germantown, NY), as described (Longo et al, 2005). RNA was extracted from the resected portion of the liver (before samples) and from the remnant liver 24 hours after resection (after samples). RNA from three animals was pooled per microarray and 2 microarrays per group were performed.
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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.
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