RNA-seq of germinal center B cell-derived cell lines after POU2F2 or POU2AF1 knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183741 | GEO | 2021/09/11
REPOSITORIES: GEO
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Project description:Pou2af1 encodes for OCA-B, a coactivator of OCT-1/2. Although primarily studied in B cells, Pou2af1 mRNA expression is induced in activated T cells and T cells from B6.129S-Pou2af1-/- mice, bearing a mixed genetic background, show impaired T cell functions, such as cytokine production and Tfh differentiation. To revisit the impact of Pou2af1 in T cells, we generated Pou2af1fl/fl mice with specific genetic disruption of Pou2af1 in hematopoietic cells, Vav-Cre, or T cells, CD4-Cre, on the B6 background. Surprisingly, T cell cytokine production was not impaired in these models, and Tfh differentiation was influenced by T cell extrinsic deletion of Pou2af1. To determine the role of Pou2af1 induction in T cells, we performed RNA-Seq on activated T cells from CD4-Cre-.Pou2af1fl/fl and CD4-Cre+.Pou2af1fl/fl mice. Apart from Pou2af1 mRNA expression, the transcriptomic profiles were remarkably comparable. Overall, this study provides strong evidence that Pou2af1 does not act as transcriptional coactivator in T cells.
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Project description:The requirement for the B cell transcription factor OCT2 (encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse but that their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This led us to examine the role of OCT2 in germinal center derived lymphomas. ShRNA knockdown showed that almost all DLBCL cell lines are addicted to the expression of OCT2 and its co-activator OCA-B. Genome-wide chromatin Immunoprecipitation analysis and gene expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL10, ELL2, XBP1, MYC, TERT and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies as well as a recurrent mutation of threonine 223 in the DNA binding domain of OCT2. This neomorphic mutation subtly alters the DNA binding preference of OCT2 leading to the transactivation of novel target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface we reveal a requirement for this protein-protein interface that might ultimately be exploited therapeutically. Our findings, combined with the predominantly B cell restricted expression of OCT2 and the absence of systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL whilst avoiding systemic toxicity.
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Project description:The requirement for the B cell transcription factor OCT2 (encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse but that their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This led us to examine the role of OCT2 in germinal center derived lymphomas. ShRNA knockdown showed that almost all DLBCL cell lines are addicted to the expression of OCT2 and its co-activator OCA-B. Genome-wide chromatin Immunoprecipitation analysis and gene expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL10, ELL2, XBP1, MYC, TERT and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies as well as a recurrent mutation of threonine 223 in the DNA binding domain of OCT2. This neomorphic mutation subtly alters the DNA binding preference of OCT2 leading to the transactivation of novel target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface we reveal a requirement for this protein-protein interface that might ultimately be exploited therapeutically. Our findings, combined with the predominantly B cell restricted expression of OCT2 and the absence of systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL whilst avoiding systemic toxicity.
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Project description:The transcriptional coregulator OCA-B is induced in stimulated naïve CD4+ T cells, where docks with transcription factor Oct1 to regulate genes such as Il2 and Ifng. OCA-B regulates its targets in cases of repeated antigen exposure, a necessary feature of autoimmunity. Polymorphisms in binding sites for Oct1, and by extension OCA-B, as associated with multiple forms of autoimmunity including autoimmune (type-1) diabetes. We hypothesized that T cell-specific OCA-B deletion would protect mice from type-1 diabetes, and that pharmacologic OCA-B inhibition would provide similar protection. We developed an Ocab (Pou2af1) conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous T1D. To clarify the mechanism, we profiled leukocytes from prediabetic islets by single-cell RNA sequencing and T cell receptor clonotype analysis.
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Project description:ATAC-seq of germinal center B cell-derived cell lines after POU2F2 or POU2AF1 knockdown
| PRJNA762047 | ENA
Project description:RNA-seq of germinal center B cell-derived cell lines after POU2F2 or POU2AF1 knockdown
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Project description:The identification of druggable therapeutic targets that preferentially promote autoimmunity remains a key goal in the field. Recent work shows that populations of memory/stem-like T cells drive autoimmunity, but the factors that generate and sustain these populations are incompletely understood. The lymphocyte-restricted transcriptional cofactor OCA-B/Pou2af1 is a regulator of CD4+ T cell memory. Here we show that T cell-intrinsic loss of OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) in both chronic and relapsing-remitting mouse models while preserving acute responses to infection with a neurotropic coronavirus. In adoptive transfer EAE driven by antigen re-encounter, T cell-specific OCA-B loss largely eliminates Th1- and Th17-mediated CNS infiltration, proinflammatory cytokine production and disease. Using an OCA-B-mCherry reporter mouse, we show that OCA-B expressing CD4+ T cells within the CNS of mice with EAE preferentially display a memory-like phenotype. Transferring these OCA-Bhi memory-like CD4+ T cells preferentially confers disease, identifying OCA-B as a marker of encephalitogenic autoreactive CD4+ T cells. Notably, in a relapsing-remitting EAE model, OCA-B T cell-deficient mice show specific protection at relapse, highlighting the potential to target OCA-B in MS patients to limit disease progression. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating T cell populations. At relapse, OCA-B loss results in the accumulation of an immunomodulatory CD4+ T cell population expressing Ccr9 and Bach2. These results highlight OCA-B as a driver of pathogenic stem-like T cells responsible for relapse and promising MS therapeutic target.
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