Federica Alberghini

Polycomb (PcG) proteins are epigenetic modifiers that modulate accessibility of genomic loci through the sequential activity of at least two functionally and biochemically distinct complexes, named Polycomb repressive complex 1 and 2 (PRC1 and PRC2), which modify histone tails to yield permanent and heritable, yet reversible, locus silencing. PcG proteins modulate expression of genes involved in multiple biological functions and their deregulation leads to aberrant differentiation of a number of cellular lineages, including the lymphoid subsets. Using a conditional gene targeting approach in vivo, we addressed the function of Ring1a and Ring1b, the catalytic subunits of PRC1, in B cell development. Selective PRC1 inactivation in transitional B cells led to aberrant differentiation and extensive transcriptional deregulation. Loss of PRC1 in germinal center (GC) B cells caused a significant reduction in their numbers and frequency. Consequently, serum titers of antigen-specific, class-switched antibodies were significantly decreased and memory B cell formation was impaired in mutant mice. Instead, mutant GC B cells showed premature onset of terminal differentiation towards the plasma cell fate and increased apoptosis. Importantly, activation of B cells with a non-Activation Induced Deaminase (AID)-inducing compound normalized the apoptotic rate of PRC1 deficient cells to wild-type levels. Together with the up-regulation of several targets belonging to the network of the GC master regulator Bcl6, this suggests that PRC1 may support GC function by co-operating in the establishment of Bcl6 transcriptional program and by participating in the repair of AID-induced DNA damage, allowing tolerance of AID genotoxic activity by GC B cells.