Histone deacetylase 3 controls a transcriptional network required for B cell maturation

Abstract

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.

TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate

“…Accordingly, the GC reaction in Tbl1xr1 LOF mice was significantly impaired, and GCB showed upregulation of BCL6 targets. Whereas Bcl6-KO completely abrogates GC formation (Hatzi and Melnick, 2014), Tbl1xr1 LOF effects are reminiscent of the milder effects observed in mice carrying NCOR/SMRT LOF mutations that disrupt interaction with HDAC3 (Jiang et al, 2017) or Hdac3 conditional deletion (Stengel et al, 2019). The difference in severity between BCL6 versus TBL1XR1/SMRT complex deficiency phenotype is likely due to SMRT/HDAC3-independent BCL6 functions such as interaction with BCOR and LSD1 (Hatzi et al, 2019).…”

Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a Rabbit Retinoblastoma Model

“…HDAC inhibitors gradually alter histone acetylation to change chromatin structure and impact gene expression. 49 , 50 These generally require chronic exposure over time to cause these downstream changes in gene expression levels leading to cell death. In contrast, the pharmacokinetics of intravitreal injection, 51 – 53 with single injections spaced out over weeks, and the rapid decline in vitreous drug levels following each injection, would not be thought to be conducive to this sort of chronic sustained change in gene expression.…”

Chidamide Suppresses the Growth of Cholangiocarcinoma by Inhibiting HDAC3 and Promoting FOXO1 Acetylation

“…Acetylation by Inhibiting HDAC3. It has been reported that HDAC3 activates the transcription of FOXO1 [22]. We proceeded in this study to investigate whether CDM induced FOXO1 acetylation by inhibiting HDAC3.…”