Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein

Lee, Chang Hoon; Melchers, Mark; Wang, Hongsheng; Torrey, Ted A.; Slota, Rebecca; Qi, Chen‐Feng; Kim, Ji Young; Lugar, Patricia L.; Kong, Hee Jeong; Farrington, Lila; Zouwen, Boris van der; Zhou, Jeff X.; Lougaris, Vassilios; Lipsky, Peter E.; Grammer, Amrie C.; Morse, Herbert C.

doi:10.1084/jem.20051450051208c

Cited by 41 publications

(62 citation statements)

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“…Therefore, we searched for other genes that regulate Bcl6. Few known regulators of Bcl6 transcription include inducers like IFN regulatory factor 8 (IRF8) (28) or repressors like IRF4 (29) and the E-box factor Mxd1/ Mad1 (30). We found that Mxd1 is significantly up-regulated (2.5-fold) in Eμ-miR-155 mice B cells as revealed by the microarray analysis and confirmed by real-time PCR (Fig.…”

Section: Bcl6 Transcription Is Indirectly Modulated By Mir-155 Througmentioning

confidence: 99%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

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

121

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Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.NfκB | Ingenuity Pathway Analysis M icroRNAs (miRNAs) are 18-24-nucleotide-long noncoding RNA molecules that regulate gene expression in many cellular processes including proliferation, differentiation, and development. Recent studies have established that expression of miRNAs is widely altered in a variety of cancers and miR-155 is one of the most frequently overexpressed miRNAs in various solid and hematological malignancies (1). miR-155 is highly upregulated in Hodgkin, primary mediastinal, and diffuse large B-cell lymphomas (DLBCL) (2, 3) and is almost absent or significantly down-regulated in primary cases of Burkitt lymphoma (4). Overexpression of bic, host mRNA of miR-155, caused increased incidence of leukemia and a decrease in latency of lymphoma development in chickens with elevated levels of MYC (5). Overexpression of miR-155 in mice B cells (Eμ-miR-155) has been shown to cause pre-B-cell leukemia/high-grade lymphoma (6), whereas deletion of bic/miR-155 in mice has been attributed to immunodeficiency and impaired T-cell-dependent antibody response (7,8). Additionally, sustained miR-155 expression in stem cell progenitors induced a myeloproliferative disease in transplanted mice (9). Despite the availability of multiple animal models and a ...

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Section: Bcl6 Transcription Is Indirectly Modulated By Mir-155 Througmentioning

confidence: 99%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

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

121

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“…IRF8 is highly expressed in mouse and human GCs (15,30) and shares a large number of common target genes in GC B cells, about half of which are also targeted by PU.1 (16). IRF8 has also been implicated in the development of B cell-driven systemic autoimmune diseases in humans and mice (31,32).…”

Section: Discussionmentioning

confidence: 99%

“…Irf8 is expressed primarily in hematopoietic cells including all stages of B cell differentiation up to terminally differentiated plasma cells (12). To determine whether IRF8 might affect expression of BCOR and vice versa, we studied transcript levels for Irf8 and Bcor in sublines of the mouse NFS202 B cell lymphoma of GC origin that express an IRF8-suppressive or a scrambled siRNA (15). Bcor transcript levels were 3-4.5-fold higher in the knockdown cell line than in the scrambled siRNA transfectants, whereas Bcl6 transcript levels were dramatically reduced more than 90% in the Irf8 knockdown cells (Fig.…”

Section: The Bcor-irf8 Complex Enhances Gene Repression By Bcl6 and mentioning

confidence: 99%

“…Previous studies demonstrated that IRF8 is involved in the regulation of Bcl6 expression in GC B cells (15). BCL6 is a transcriptional repressor with critical roles in several immunological processes including B and T cell functions, especially GC development and generation.…”

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confidence: 99%

“…Analyses of B lineage cells showed that IRF8 contributes to a series of transcriptional networks affecting the earliest stages of lineage commitment and specification in the bone marrow (12), rearrangements at the immunoglobulin (Ig) locus (13), and distribution of mature cells into splenic B cell subcompartments (14). IRF8 was shown to exert its influences on the germinal center (GC) reaction, class switch recombination, and plasma cell development through partnering with PU.1 and IRF4 to promote the activation of Aicda and Bcl6, genes central to the maintenance of the B cell program, while repressing genes such as Prdm1 that promote terminal differentiation (15,16).…”

mentioning

confidence: 99%

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Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

Yoon

Feng

Kim

et al. 2014

Journal of Biological Chemistry

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Background: Protein partnerships regulate specific functions of cells. BCOR protein-protein interactions are critical to aspects of B cell biology. Results: IRF8 pairs with BCOR in the nucleus to enhance its transcriptional repressive activity. Conclusion: Partnering of IRF8 with BCOR defines a novel mechanism for controlling B cell gene expression. Significance: Understanding gene regulation in specific cell types requires identification of protein complexes that modulate expression.

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Memory B cells: Effectors of long‐lived immune responses

2009

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Immunological memory is the phenomenon whereby B and T cells have the unique ability to respond with heightened kinetics and efficacy to subsequent encounter with Ag relative to the initial exposure. In this review, we examine recent developments in the phenotypic characterisation of memory B cells, with an emphasis on the definition and functional properties of memory B-cell subsets in humans. Gene expression differences are also considered in light of the unique functional and survival properties of memory B cells, and mutations that alter memory formation and function are also examined. Finally, we consider recent advances in the understanding of germinal center B-cell differentiation through analysis of transcription factor networks operating in these B cells. Key words: B cells . Cell differentiation . Memory cells IntroductionThe ability of the immune system to ''remember'' previous encounters with pathogens, and to respond with heightened kinetics and efficacy compared with the initial exposure, is a defining feature of the adaptive immune response of higher vertebrates. The contribution of B cells to immunological memory encompasses two distinct populations of cells that are generated during primary immune responses, long-lived plasma cells (PC), which continue to secrete high levels of neutralising Ig for protracted periods of time well after Ag clearance, and memory B cells, which can rapidly proliferate and differentiate into PC following recurrent exposure to the initial immunising Ag, thereby simultaneously increasing the precursor frequency of Ag-specific memory B cells and enriching the pool of Ag-specific Ig [1][2][3][4]. The ability of naïve B cells to differentiate into memory and PC underlies the success of most -if not all -vaccines currently in use. Despite this, and the fact that we have known about the phenomenon of humoral immunity for centuries, we still do not have a thorough understanding of the biology of memory B cells. Here, we will highlight recent advances, and outstanding questions, in elucidating some of the critical aspects underlying the generation, function and maintenance of memory B cells. Development of serological memory is dependent on germinal centresFollowing initial interactions between protein Ag, naïve B cells and other cells within the lymphoid tissue microenvironment such as CD4 1 T cells, macrophages and DC, the Ag-specific naïve B cells then undergo one of two fates: some of them rapidly differentiate into short-lived PC, which provide a first wave of defence against the invading pathogen, while others migrate to the B-cell follicle and seed a germinal centre (GC) [1][2][3][4][5]. Within GC several cardinal molecular processes necessary for the evolution of long-lived serological immunity take place: somatic hypermutation (SHM) and class switch recombination (CSR) of the Ig V and C region genes, respectively, expressed and secreted [5,8,10,[19][20][21][22][23][24][25][26]. Although these analyses are largely restricted to in vitro experiments, they yielded impo...

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Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein

Cited by 41 publications

References 0 publications

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

Memory B cells: Effectors of long‐lived immune responses

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