Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors

Kwon, Hyung Bae; Thierry-Mieg, Danielle; Thierry‐Mieg, Jean; Kim, Hyoung‐Pyo; Oh, Jangsuk; Tunyaplin, Chainarong; Carotta, Sebastian; Donovan, Colleen E.; Goldman, Matthew L.; Tailor, Prafullakumar; Ozato, Keiko; Levy, David E.; Nutt, Stephen L.; Calame, Kathryn; Leonard, Warren J.

doi:10.1016/j.immuni.2009.10.008

Cited by 322 publications

(378 citation statements)

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“…These findings indicate that Bach2 directly and/or T-cell intrinsically suppresses effector memory-related genes in naive T cells. Interestingly, these are genes induced by cellular stresses; oxidative stress induces S100a and HO-1 expression (24,31), and LPS and cellular stress induce Blimp-1 (32,33), HO-1, and ST-2. Such stresses can also activate Nrf2 (7), which may also regulate these genes, although Nrf2 is a transcriptional activator whereas Bach2 is a repressor.…”

Section: Discussionmentioning

confidence: 99%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

151

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The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (−/−) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2 −/− naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2 −/− naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. Kruppel-like factor 2 (KLF2) is one of those TF, which regulates the expression of the sphingosine-1-phosphate receptor-1 (S1pr1) in SP cells (2). S1pr1 is required for the egress of SP cells from the thymus, and thus KLF2-deficient (−/−) SP cells accumulate in the thymus. KLF2 positively regulates S1pr1 expression through direct binding to its promoter. KLF2 −/− mice also develop an unusual population of innate-like CD8 +

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Section: Discussionmentioning

confidence: 99%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

151

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“…The other possible reason is that Ramos cells, a lymphoma cell line, have impaired differentiation, as do tumor cells. BLIMP1 expression is induced by the cooperation of transcription factors, such as STAT3, IRF-4, and NF-kB (27,28). Normal GCB cells express these factors properly and are ready to respond to BCR stimulation, which might enable a rapid and substantial increase in BLIMP1 expression in response to even transient PAX5 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

Yasuda

Hayakawa

Kurahashi

et al. 2012

The Journal of Immunology

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Plasma cell differentiation is initiated by Ag stimulation of BCR. Until BCR stimulation, B lymphocyte-induced maturation protein 1 (BLIMP1), a master regulator of plasma cell differentiation, is suppressed by PAX5, which is a key transcriptional repressor for maintaining B cell identity. After BCR stimulation, upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed and thought to be the trigger of plasma cell differentiation; however, the trigger that derepresses BLIMP1 expression is yet to be revealed. In this study, we demonstrated PAX5 phosphorylation by ERK1/2, the main component of the BCR signal. Transcriptional repression on BLIMP1 promoter by PAX5 was canceled by PAX5 phosphorylation. BCR stimulation induced ERK1/2 activation, phosphorylation of endogenous PAX5, and upregulation of BLIMP1 mRNA expression in B cells. These phenomena were inhibited by MEK1 inhibitor or the phosphorylation-defective mutation of PAX5. These data imply that PAX5 phosphorylation by the BCR signal is the initial event in plasma cell differentiation.

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“…1,[21][22][23][24][25] Signals that can activate PRDM1 expression include those from cytokines (IL5, IL6, IL-10, and IL-21), toll-like receptors, and antigen receptors. AP-1, NF-B, IRF4/MUM1, STAT3, PU1, and C/EBP␤ induce PRDM1 transcription, while BCL6, PAX5, and BACH2 repress PRDM1 transcription.…”

Section: Discussionmentioning

confidence: 99%

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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Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors

Cited by 322 publications

References 35 publications

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

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

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