Epigenetic control of the protocadherin-gamma locus provides a potential source of cell surface codes in B cell differentiation

Abstract

Abstract Cellular adhesion plays an important role in determining homing and retention of cells to specific locations. Antibody-secreting plasma cells (PCs) depend on access to niche microenvironments for survival, but the factors that control the adhesion behaviour of different PCs are incompletely understood. We noted that cadherin superfamily protocadherin (PCDH) genes showed a dynamic pattern of regulation during differentiation of human PCs. Clustered PCDHs are split into 3 gene loci (α, β and γ). Choice of variable first exons, which encode the extracellular domain is determined by selective promoter usage. This is controlled by CTCF and enhancer looping. In neurons, PCDH expression generates single cell identity codes important for synapse formation. Tracking differentiation from B cell to PC stage, ATAC-seq demonstrated selective accessibility over the PCDHG but not PCDHA or PCDHB loci. ChIP-seq for CTCF, H3K4me3 and H3K27ac revealed active promoter marks and CTCF interactions within the PCDHG locus. Flow cytometry confirmed heterogenous expression of PCDHG family members during PC differentiation in line with mRNA patterns. Consistent with post-translational regulation, PCDHG surface expression was additionally increased by ADAM protease inhibition. We conclude that the B cell lineage shows selective epigenetic accessibility at the PCDHG locus and expression of PCDHG family members upon differentiation to the PC state. This is coupled with patterns of CTCF occupancy implicated in regulating surface identity codes. We conclude that epigenetic control of the PCDHG locus provides a potential source of cell surface codes amongst differentiating PCs.