Title: Understanding the role of classs IIa-histone deacetylases in normal B-cell development and function.
Funder: Cancer Research UK

Abstract: B-lymphocytes (B-cells) make antibodies that bind and neutralise bacterial toxins, viruses and bacteria. However, defects in B-cell development, activation and antibody responses can lead to lymphoproliferative diseases. Understanding basic mechanisms that regulate normal B-cell activation, development and function is crucial for understanding the molecular basis of B-cell malignancies and for identifying novel therapeutic targets for these diseases. Signals from the B-cell antigen-receptor (BCR) and its precursor (preBCR) induce changes in gene transcription that determine the fate and function of developing B-cells. We have identified a novel, indirect mechanism by which the BCR can control the function of transcriptional regulators in B-cells. Stimulation of the BCR activates PKD serine kinases, leading to the phosphorylation and nuclear exclusion of class IIa-histone deacetylases (HDACs). This relieves class IIa-HDAC-mediated repression of myocyte enhancer factor-2 (MEF2) transcription factors, key regulators of cell growth, differentiation and survival. Aberrant recruitment of HDACs to chromatin by leukaemia and lymphoma-associated oncogenic fusion proteins is linked to deregulated gene expression and cellular transformation and HDAC inhibitors are in clinical use as anti-cancer therapeutics in haematological malignancies. However the exact biological roles of HDACs in regulating normal B-cell development and function is not known. A clearer understanding of the role of specific HDACs is required in order to understand and intervene in B-cell malignancies. The goal of this research proposal is to investigate the role of class IIa-HDACs in normal murine B-cell development and humoral immune responses. We hypothesise that class IIa-HDAC/MEF2 transcriptional regulators have a key role in regulating B-cell development, activation and antibody effector responses. We will test this hypothesis by analysing the role of class IIa-HDACs in regulating B-cell lineage commitment, maturation and activation responses using both in vitro B-cell generation systems (where gain and loss of function class IIa-HDAC mutant proteins are introduced into murine B-cell progenitors by retroviral infection) and genetically modified models (HDAC7 knockout mice). We will also identify and characterise genes that are directly repressed by endogenous HDAC7 in normal naïve murine B-cells (using ChIP-sequencing technology). These experiments will provide important insight into the role of class IIa-HDAC transcriptional repressors and how they influence specific gene expression programs to regulate normal B-cell development and humoral immune responses. This will enhance our understanding of basic B-cell biology and may have important implications for understanding of and therapeutic intervention in B-cell diseases such as leukaemia, lymphoma, myeloma, autoimmunity and primary antibody deficiencies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS