Molecular regulation of B-cell differentiation is critical for formation of immune memory and becomes dysregulated in B-cell lymphomas. Alterations in the genomic landscape that allow or restrict access of transcription factors are critical to enact gene expression profiles that in turn drive B-cell differentiation. Chromatin accessibility can be modulated by enzymes that modify the N-terminal tail of histones. For example, the Trithorax group protein MLL1 forms complexes to trimethylate H3K4, permitting transcription, whereas the two Polycomb repressor complexes work together to repress gene expression through di/trimethylation of H3K27 (PRC2) and mono-ubiquitination of histone H2AK119 (PRC1). Changes in H3K4me3 and H3K27me3 patterns during B-cell differentiation correlates with function, therefore we investigated the temporal and spatial requirements of MLL1, canonical PRC1 and PRC2 in B-cell fate decisions during acute and chronic immune responses.
Deletion of the PRC2 member EED (Eed^f/fCd23^Cre/+ mice) resulted in a complete absence of GC and B-cell memory following immunisation or influenza infection, similar to its binding partner EZH2. Mll1^f/fCd23^Cre/+ mice also could not mount an effective GC response to immunisation, yet their plasmablast response remained intact in vivo. In contrast, mice deficient in the canonical PRC1 member BMI-1 (Bmi1^f/fCd23^Cre/+) had normal GC formation but was required for plasmablast responses. Surprisingly, the requirement for EED in a chronic persisting infection differed from acute responses. Eed^f/fCd23^Cre/+ mice infected with LCMV-WE had reduced GC responses. However, Eed^f/fCd23^Cre/+ mice infected with LCMV-Docile or P. chabaudi had normal GC formation. In contrast, Mll1^f/fCd23^Cre/+ mice had normal GC responses to acute LCMV strain but reduced GCs in chronic infection. Together, our data demonstrate the differential requirements of these complexes in B-cell fate decisions, as well as suggest normal epigenetic regulatory checks are subverted in chronic infections.