Investigating Unknown Regulators of Plasma Cell Differentiation Using a Novel IRF4 Haploinsufficient Mouse Model 2069

Description High expression of the IRF4 transcription factor (TF) is required for upregulation of the Blimp-1 TF to commit an activated B cell toward the plasma cell (PC) fate. Our lab has shown in B cell-specific IRF4 haploinsufficient mice, not only is PC quantity expectedly diminished, but surprisingly, PC quality was impaired as well. Although these cells display the hallmarks of a functional PC, they fail to develop into complete PCs, suggesting there exists unknown genetic barriers to full PC development. We propose to use the IRF4 haploinsufficient model as a novel tool to investigate unknown genetic PC checkpoints. We hypothesize that dynamic accumulation of IRF4 fine-tunes the expression of agonistic and antagonistic PC regulators to dictate full PC differentiation and activity. We will collect genome-wide measurements of gene expression pattern, chromatin accessibilities, and IRF4 binding of wildtype and IRF4+/- PCs using RNA-, ATAC-, and ChIP-sequencing technologies. We will then integrate these datasets to establish a whole genome landscape of IRF4 activity and investigate differential patterns between wildtype and IRF4+/- PCs. Through differential analyses, we have identified several putative regulators including, Junb and miR-155, and continued investigation will enable us to determine direct or indirect IRF4 regulation. The goal of this study is to establish a more extensive gene regulatory network of PC differentiation and find yet-unknown barriers to PC differentiation. Funding Sources Supported by the Lodric Madox Fellowship, Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)