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Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Stengel KR, Bhaskara S, Wang J, Liu Q, Ellis JD, Sampathi S, Hiebert SW
(2019) Nucleic Acids Res 47: 10612-10627
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Base Sequence, Cell Differentiation, Gene Expression Regulation, Gene Regulatory Networks, Histone Deacetylase Inhibitors, Histone Deacetylases, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcription, Genetic, Up-Regulation
Show Abstract · Added October 25, 2019
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
1 Communities
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18 MeSH Terms
B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
(2018) J Immunol 200: 2627-2639
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunoglobulin G, Immunologic Memory, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mutation, Plasma Cells, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription Factors
Show Abstract · Added March 14, 2018
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
2 Members
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17 MeSH Terms
Controlling COR competence: BCL-6 regulates neurogenesis and tumor suppression.
Chiang C, Ihrie RA
(2014) Cancer Cell 26: 773-774
MeSH Terms: Animals, DNA-Binding Proteins, Humans, Medulloblastoma, Neurogenesis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Signal Transduction, Sirtuin 1
Show Abstract · Added January 26, 2015
In this issue of Cancer Cell, Tiberi and colleagues describe a tumor-suppressor role for BCL6. In the cerebellum, BCL6 is required for the transition from proliferative precursor cell to a more differentiated immature neuron through repressing the expression of Hedgehog effectors, thus controlling a pathway that is aberrantly activated in medulloblastoma.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
2 Members
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10 MeSH Terms
A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
Hatzi K, Jiang Y, Huang C, Garrett-Bakelman F, Gearhart MD, Giannopoulou EG, Zumbo P, Kirouac K, Bhaskara S, Polo JM, Kormaksson M, MacKerell AD, Xue F, Mason CE, Hiebert SW, Prive GG, Cerchietti L, Bardwell VJ, Elemento O, Melnick A
(2013) Cell Rep 4: 578-88
MeSH Terms: Animals, B-Lymphocytes, Cell Line, Tumor, DNA-Binding Proteins, Heterografts, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Models, Molecular, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Signal Transduction
Show Abstract · Added March 26, 2014
The BCL6 transcriptional repressor is required for the development of germinal center (GC) B cells and diffuse large B cell lymphomas (DLBCLs). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B cells is unknown. We find that in B cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are (1) the formation of a unique ternary BCOR-SMRT complex at promoters, with each corepressor binding to symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features, and (2) the "toggling" of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 deacetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
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12 MeSH Terms
Anticancer therapy SMRT-ens up: targeting the BCL6-SMRT interaction in B cell lymphoma.
Compton LA, Hiebert SW
(2010) Cancer Cell 17: 315-6
MeSH Terms: DNA-Binding Proteins, Humans, Lymphoma, B-Cell, Nuclear Receptor Co-Repressor 2, Precision Medicine, Proto-Oncogene Proteins c-bcl-6
Show Abstract · Added March 7, 2014
Transcription factors have proven to be difficult targets for the development of small-molecule drugs. In this issue of Cancer Cell, Cerchietti et al. identify and characterize a specific, small-molecule inhibitor of BCL6, an oncogenic transcriptional repressor, that has high clinical promise for treating diffuse large B cell lymphoma.
Copyright 2010 Elsevier Inc. All rights reserved.
1 Communities
1 Members
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6 MeSH Terms
Translating the histone code into leukemia.
Linggi BE, Brandt SJ, Sun ZW, Hiebert SW
(2005) J Cell Biochem 96: 938-50
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Chromatin, Chromosomes, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Histone Acetyltransferases, Histone Deacetylases, Histones, Humans, Leukemia, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-6, Recombinant Fusion Proteins, Translocation, Genetic
Show Abstract · Added March 5, 2014
The "histone code" is comprised of the covalent modifications of histone tails that function to regulate gene transcription. The post-translational modifications that occur in histones within the regulatory regions of genes include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These modifications serve to alter chromatin structure and accessibility, and to act as docking sites for transcription factors or other histone modifying enzymes. Several of the factors that are disrupted by chromosomal translocations associated with hematological malignancies can alter the histone code in a gene-specific manner. Here, we discuss how the histone code may be disrupted by chromosomal translocations, either directly by altering the activity of histone modifying enzymes, or indirectly by recruitment of this type of enzyme by oncogenic transcription factors. These alterations in the histone code may alter gene expression pattern to set the stage for leukemogenesis.
2005 Wiley-Liss, Inc.
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19 MeSH Terms
Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program.
Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, Giltnane JM, Yang L, Zhao H, Calame K, Staudt LM
(2002) Immunity 17: 51-62
MeSH Terms: Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, DNA-Binding Proteins, Gene Expression Profiling, Gene Expression Regulation, Humans, Immunoglobulin Class Switching, Mice, Models, Immunological, Oligonucleotide Array Sequence Analysis, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger, Receptors, Antigen, B-Cell, Repressor Proteins, Signal Transduction, Spleen, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Blimp-1, a transcriptional repressor, drives the terminal differentiation of B cells to plasma cells. Using DNA microarrays, we found that introduction of Blimp-1 into B cells blocked expression of a remarkably large set of genes, while a much smaller number was induced. Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B and Id3, that regulate signaling by the B cell receptor. Blimp-1 also inhibited immunoglobulin class switching by blocking expression of AID, Ku70, Ku86, DNA-PKcs, and STAT6. These findings suggest that Blimp-1 promotes plasmacytic differentiation by extinguishing gene expression important for B cell receptor signaling, germinal center B cell function, and proliferation while allowing expression of important plasma cell genes such as XBP-1.
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24 MeSH Terms