The “EPI-B-PLASMADIFF” project (36 months, 4 teams) will address scientific issues pertinent to the B-cell-lineage and their implications in immunopathology, with specific focus on antibody-secreting plasma cells. Antibody secreting cells are critical effector cells and long-lived sentinels for immune memory. B cell maturation should be tightly regulated to ensure efficient immune response without autoimmunity or immune deficiency. On the transcriptional level, the differentiation of B cells into plasma cells is associated with substantial and coordinated changes in the gene expression profile, which fall into two main categories: the loss of B cell-associated transcripts and the acquisition of plasma cell gene expression program. Although the role of the complex network of transcription factors involved in PCD has been investigated, the mechanisms regulating key plasma cell differentiation transcription networks remain poorly known. Little is known about the role of epitranscriptomic modifications in B to plasma cell differentiation and how it could regulate fundamental processes during normal plasma cell differentiation. In this proposal, we seek to characterize and understand the epitranscriptomic remodeling and the transcriptional, translational and epigenetic impacts during B to plasma cell differentiation with a particular focus on m6A modifications. We would like to reveal both the pathways involved in this remodeling and their downstream effects. The rationale of our project is in line with the identification of major epitranscriptomic changes during plasma cell differentiation, which was identified by mass spectrometry, and preliminary data supporting a role of the enzymes involved in m6A modification in the biology of plasma cells. We plan to identify upstream pathways mediating these changes and their downstream transcriptional and translational impacts. These studies will take advantage of a unique combination of powerful models and new technologies that are fully mastered by the four partners of the project.