Blimp-1/Prdm1 Alternative Promoter Usage during Mouse Development and Plasma Cell Differentiation

Morgan, Marc A.; Magnúsdóttir, Erna; Kuo, Tracy C.; Tunyaplin, Chai; Harper, J. A.; Arnold, Sebastian J.; Calame, Kathryn; Robertson, Elizabeth J.; Bikoff, Elizabeth K.

doi:10.1128/mcb.00670-09

Cited by 55 publications

(65 citation statements)

References 86 publications

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“…It is interesting that higher levels of PRDM1␣ mRNA are found in DLBCL harboring PRDM1 inactivating mutations compared with those without such mutations. Although this observation may simply be attributed to a loss of the negative feedback signals due to total absence of PRDM1, 45 the possibility that stronger PRDM1 induction signals are received by these cells before inactivating gene mutation events cannot be excluded. If the later scenario is indeed true, mutational inactivation rather than miRNA alone may be necessary to down-regulate PRDM1 to levels that promote outgrowth of lymphoma cells owing to the higher levels of PRDM1 transcripts.…”

Section: Discussionmentioning

confidence: 98%

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Nie

Zhang

Allawi

et al. 2010

The American Journal of Pathology

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PRDM1/Blimp-1, a master regulator for B cell terminal differentiation, is a putative tumor suppressor in diffuse large B cell lymphomas (DLBCL). Inactivating mutations of PRDM1 have been previously identified in a subset of nongerminal center B cell-like (GCB) DLBCL. We investigated the presence of alternative mechanisms of down-regulating PRDM1 in a cohort of 25 primary DLBCL and six DLBCL cell lines. While some DLBCL, predominantly the GCB-type, showed low levels of both PRDM1␣ mRNA and protein, presumably as a result of direct transcription repression, discordant expressions between the two were identified in a subset of DLBCL without PRDM1 mutations, the primarily non-GCB type, consistent with translational down-regulation. This subset of DLBCL exhibits relatively high PRDM1␣ mRNA levels but low levels of PRDM1. Data obtained from expression analysis , luciferase reporter assays , and transfection experiments support a role of targeting of PRDM1 by microRNA let-7 family in mediating this down-regulation. Let-7 , in particular let-7b , is overexpressed in DLBCL relative to normal GCB cells , suggesting that it is deregulated. Thus , abnormal epigenetic down-regulation of PRDM1 by let-7 and other microRNAs may represent an alternative mechanism of reducing normal PRDM1 function in a subset of DLBCL with relatively high PRDM1␣ mRNA expression and unmutated PRDM1. PRDM1/Blimp-1 is a master transcriptional regulator for terminal differentiation of B cells into plasma cells. [1][2][3][4] It also plays a critical role in effector and memory T-cell differentiation, 1,3,5 myeloid cell development, 6 dendritic cell development, 7 and epithelial cell differentiation. 8 Inactivating mutations that result in the generation of a severely truncated nonfunctional PRDM1 are found in about 20% of the diffuse large B cell lymphomas (DLBCLs) of the nongerminal center B cell (GCB) subtype 9,10 and also in about 19% of the primary DLBCL of the central nervous system. 11 These mutations are associated with deletion of the other paired PRDM1 allele at chromosome 6q21. These findings are consistent with PRDM1 being a DLBCL tumor suppressor gene and imply an important role of impairment of terminal B cell differentiation in DLBCL pathogenesis. However, many DLBCLs lack genetic alterations in PRDM1. Posttranscriptional down-regulation of PRDM1 in DLBCL has been suggested, but no systematic evaluation was performed. 10 In this study, we investigated this possibility in detail by comparative and quantitative analysis of PRDM1 mRNA and protein expression in different subgroups of DLBCL. We concluded that low or absent PRDM1 expression is a common phe-

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Section: Discussionmentioning

confidence: 98%

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Nie

Zhang

Allawi

et al. 2010

The American Journal of Pathology

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“…Our demonstration of TGF-β-mediated decline in BLIMP1 levels in CD8 + T cells is novel, and the molecular basis of this downregulation remains unaddressed. It is currently unknown whether Prdm1, the gene encoding BLIMP1, is a direct SMAD target (50). However, based on previous studies demonstrating that TGF-β1 inhibits the activity of NF-κB (51), a molecule that plays a direct role in modulating BLIMP1 expression (50), it will be critical to ascertain whether a similar mechanism suppresses CD8 + T cell polyfunctionality in aged mice.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition

Bhadra¹,

Moretto

Castillo

et al. 2014

J. Clin. Invest.

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Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8 + T cell polyfunctionality, primarily due to CD8 + T cell-extrinsic deficits, and that reduced CD8 + T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8 + T cell survival and polyfunctionality were suppressed by highly elevated TGF-β1. Furthermore, TGF-β depletion reduced effector CD8 + T cell apoptosis in both young and aged mice and enhanced effector CD8 + T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-β signaling in CD8 + T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-β1 promote apoptosis of CD8 + effector T cells and high TGF-β1 levels associated with age result in both CD8 + T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-β levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-β represents an evolutionarily conserved negative regulator of the immune response in aging organisms.

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“…For both constructs, an hsv-tk cassette was inserted outside the 3= homology region. Gene targeting was performed in CCE mouse embryonic stem cells as described previously (55). Targeted clones were identified by Southern blotting and transiently transfected with pMC1-Cre to remove the drug resistance cassette.…”

Section: Methodsmentioning

confidence: 99%

Alternative Splicing Regulates Prdm1/Blimp-1 DNA Binding Activities and Corepressor Interactions

Morgan

Mould

et al. 2012

Molecular and Cellular Biology

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Prdm1/Blimp-1 is a master regulator of gene expression in diverse tissues of the developing embryo and adult organism. Its C-terminal zinc finger domain mediates nuclear import, DNA binding, and recruitment of the corepressors G9a and HDAC1/2. Alternatively spliced transcripts lacking exon 7 sequences encode a structurally divergent isoform (Blimp-1⌬exon7) predicted to have distinct functions. Here we demonstrate that the short Blimp-1⌬exon7 isoform lacks DNA binding activity and fails to bind G9a or HDAC1/2 but retains the ability to interact with PRMT5. To investigate functional roles of alternative splicing in vivo, we engineered novel mouse strains via embryonic stem (ES) cell technology. Like null mutants, embryos carrying a targeted deletion of exon 7 and exclusively expressing Blimp-1⌬exon7 die at around embryonic day 10.5 (E10.5) due to placental defects. In heterozygous ⌬exon7 mice, there is no evidence of dominant-negative effects. Mice carrying a knock-in allele with an exon 6-exon 7 fusion express full-length Blimp-1 only, develop normally, are healthy and fertile as adults, and efficiently generate mature plasma cells. These findings strongly suggest that the short Blimp-1⌬exon7 isoform is dispensable. We propose that developmentally regulated alternative splicing is influenced by chromatin structure at the locus and fine-tunes Blimp-1's functional capabilities.

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Blimp-1/Prdm1 Alternative Promoter Usage during Mouse Development and Plasma Cell Differentiation

Cited by 55 publications

References 86 publications

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition

Alternative Splicing Regulates Prdm1/Blimp-1 DNA Binding Activities and Corepressor Interactions

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