Epigenetic Programming of B cell Terminal Differentiation

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DESCRIPTION (provided by applicant): Antibody generation and secretion by B cells provides the basis for humoral immunity. Antibodies bind viral, bacterial and parasitic epitopes facilitatin antigen neutralization and clearance. This immune function results in protective immunity to the host and is exploited to prevent disease by the practice of vaccination. However, very young and old individuals often fail to produce a protective immune response1. Conversely, uncontrolled B cell differentiation can result in hematological malignancy or production of autoreactive antibodies. B cell differentiation is initiated by binding of extracellular stimuli to cellular receptors that trigger a signaling cascade resulting in the induction of transcription factors that reprogram B cells to secrete antibody. Transcription factor function is restricted by the availability of DNA through epigenetic modifications, which are covalent chemical additions to DNA and histones that control the accessibility of chromatin. Epigenetic modifications are heritable through the cell cycle and maintain specific gene expression programs, such as that required to maintain B cell identity. While the epigenetic programming of many hematopoietic processes have been extensively studied2-4, comparatively little work has been conducted to understand the epigenetic mechanisms that govern B cell terminal differentiation into antibody secreting plasma cells. In the following application we propose that epigenetic reprogramming contributes to the humoral immune response. We hypothesize that Lsd1, a histone 3 lysine 4 (H3K4) demethylase, silences the B cell gene expression repertoire by interacting with Blimp1, a key transcription factor in the development of plasma cells. B cell conditional deletion of Lsd1 in mice resulted in diminished plasma cell responses. Genes repressed during B cell differentiation were preferentially enriched for H3K4me1 prior to differentiation and in at least the case of major histocompatibility complex class II (MHCII), were derepressed in Lsd1-deficient plasma cells. These data suggest that Lsd1 epigenetically facilitates reprogramming of B cells into plasma cells. We pose that this is by repression of B cell enhancers, first through demethylation of H3K4me1/2 and subsequently by de novo DNA methylation5,6. We aim to test these hypotheses using genetic models currently in our laboratory in combination with cellular and molecular analyses. The results of these studies will determine the functional and phenotypic impact of Lsd1 in plasma cell formation, reveal Lsd1-induced epigenetic modifications at key B cell genes during plasma cell differentiation, and determine how these epigenetic changes impact the plasma cell gene expression program. Data from this project will illuminate how the humoral immune system is epigenetically reprogrammed in response to antigenic challenge and provide insight into how it can be modulated to improve vaccine design and for the treatment of disease.