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HDAC7 is essential in early pre-germinal center formation and its deregulation is associated with DLBCL [GC]

ABSTRACT: Histone deacetylase HDAC7 is required for early B cell development and governs the acquisition of B cell progenitors gene identity. In addition, HDAC7 has been identified as a novel biomarker and prognosis factor in infant pro-B-ALL. However, its role in mature B cell biology and associated malignancies is unknown. Here, by using a conditional mouse model for specific deletion in activated B cells, we demonstrate that HDAC7 is essential for the entry and initiation of the germinal center (GC) reaction. HDAC7 deficiency results in the blockade of B cell development at the pre-GC stage, leading to the generation of aberrant GC B cells, diminished class switch recombination and plasma cell formation. We demonstrate that, while it is generally underexpressed in diffuse large B cell lymphoma (DLBCL) tumors, the low expression of HDAC7 is associated with a poor prognosis of the patients. Importantly, exogenous expression of HDAC7 in DLBCL cell lines reduces the proliferative capacity of these latter, as well as DLBCL tumorigenecity in vivo. In summary, our data revealed first, the essential function of HDAC7 in the establishment of the GC, and second, the potential contribution of HDAC7 deregulation in DLBCL development.

ORGANISM(S): Mus musculus

PROVIDER: GSE228735 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Title of Publication: Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes Abstract of publicaton: CD4/CD8 double-positive (DP) thymocytes express the transcriptional repressor Histone Deacetylase 7 (HDAC7), a class IIa HDAC that is exported from the cell nucleus after T cell receptor (TCR) engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in thymocytes, and regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAP kinase activity that contributes to the observed loss of viability. Remarkably, the activity of Protein Kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining auto-excitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. Goal of Microarray experiment: We did these experiments to determine how alteration of the function of HDAC7, a site-specific and signal-dependent repressor of transcription, changes gene expression in CD4/CD8 DP thymocytes. Three biological replicate samples were prepared for each non-wild type mouse strain (Samples 7-18). Six biological replicates were prepared for the wild type strain (Samples 1-6). Total RNA was prepared from isolated CD4/CD8 Double-positive thymocytes and labeled with the Affymetrix Whole-Transcript labeling protocol. Labeled probes were hybridized to one Affymetrix Mouse Gene 1.0ST array each. Data from .cel files were normalized using RMA, in normalization groups representing each of the binary comparisons made. These binary comparisons between sample groups represent gene expression changes due to loss of HDAC7 (samples 1-3 vs. 7-9), transgenic expression of an HDAC7-VP16 fusion protein (samples 4-6 vs. 10-12), positive thymic selection (samples 1-6 vs. samples 11-15), and negative thymic selection (Samples 11-15 vs. samples 16-18).

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HDAC7 is essential in early pre-germinal center formation and its deregulation is associated with DLBCL [GC]

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