METABOLIC-DEPENDENT HISTONE ACETYLATION IN B CELL PATHOPHYSIOLOGY

B lymphocytes are the core of humoral immunity. Specification of hematopoietic progenitors into antibody-secreting B cells is finely coordinated by cytokines, chemokines and transcription factors that act in concert with chromatin-remodeling enzymes. The latter are impacted by the availability of metabolites serving as their obligate substrates/co-factors. Levels of histone acetylation, which is invariably associated with active transcription, are in equilibrium with the nucleo-cytoplasmatic pool of acetyl-CoA, the unique acetyl donor for protein post-translational modification. The present thesis interrogates the metabolic control on histone acetylation during B cell development. As both metabolic and epigenetic reprogramming are amenable to therapeutic targeting, these findings illuminate novel strategies to fine tune the immune humoral response. I also unravel the molecular basis of lymphomagenesis and age-associated humoral dysfunctions. This work unveiled a metabolic-epigenetic signaling circuit that promotes B cell proliferation and commitment to the germinal center (GC) reaction, a process featuring antibody affinity maturation and terminal differentiation of B lymphocytes. Mechanistically, B-T lymphocyte entanglement activates the acetyl-CoA producing enzyme ATP Citrate Lyase (ACLY), thereby promoting Histone 3 Lysine 27 (H3K27) and Histone 4 (H4) acetylation. Accordingly, GC B lymphocytes display superior H3K27 and H4 acetylation in vivo. Conversely, B cell-specific Acly deletion decreases histone acetylation levels. T-dependent signaling cues increase acetyl-CoA levels in ex vivo stimulated B lymphocytes and isotope tracing revealed striking contribution of microenvironmental lactate, which is abundant at immune sites, to de novo acetyl-CoA production and H3K27 acetylation. Mechanistically, lactate-derived pyruvate enters the mitochondria of activated B cells to feed the malate-citrate shuttle, ultimately satisfying increasing demand for acetyl-CoA. Genome-wide mapping (CUT&Tag) showed that lactic acid-mediated H3K27 acetylation induces Cbl signaling, which controls B cell ability to coordinate proliferation and terminal differentiation at GCs. Moreover, the gene encoding for the most well characterized lactate importer, SLC16A1, is specifically overexpressed in proliferating GC B cells according to single-cell transcriptomic profiling. Intriguingly, metabolic control over GC B cell histone acetylation is lost during physiological aging in both humans and mice. This underlies poor immunity in the elderly. Immunohistochemistry analysis of secondary lymphoid organs revealed global depression of histone acetylation in aged GC B cells, which however retain intact sensitivity to exogenous stimulation. This might be linked to age-related fluctuations of microenvironmental lactate in aged organisms and/or to decreased expression of the lactate importer Slc16a1 in aged GC B cells. GCBCs feature phenotypic hallmarks of cancer which render them extremely susceptible to malignant transformation. Indeed, they are the cell of origin for Diffuse Large B Cell Lymphoma (DLBCL), the most common and most aggressive type of Non-Hodgkin’s lymphoma. I found that DLBCL cells hijack ACLY-dependent histone acetylation to sustain hyperproliferation. I documented lactate-dependent histone hyperacetylation in the GC-DLBCL cell lines, which are sensitive to ACLY inhibition. In line with that, SLC16A1 expression correlates with reduced survival in DLBCL patients. In summary, this research significantly advances our understanding of the epigenetic control of B cell pathophysiology by revealing a crucial link between lactic acid, acetyl-CoA metabolism and histone acetylation. This paves the way for the modulation of B cell function in physiological aging and DLBCL through dietary interventions that synergize with epigenetic mechanisms.