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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.
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.
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.
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.
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.
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.
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.